pharmaceuticals

Review
Levothyroxine Interactions with Food and Dietary
Supplements–A Systematic Review
Agnieszka Wiesner 1 , Danuta Gajewska 2 and Paweł Paśko 1, *

1 Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College,
9 Medyczna, 30-688 Kraków, Poland; agnieszka.wiesner@doctoral.uj.edu.pl
2 Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences -
SGGW (WULS), 159C Nowoursynowska, 02-787 Warsaw, Poland; danuta_gajewska@sggw.edu.pl
* Correspondence: p.pasko@uj.edu.pl; Tel.: +48-12-620-5670

Abstract: Levothyroxine (L-thyroxine, L-T4) is a drug of choice for treating congenital and primary
hypothyroidism. Although clinically significant interactions between L-T4 and food can alter the
safety and efficacy of the treatment, they still seem to be generally underestimated by patients,
physicians and pharmacists. This review aimed to investigate the effects of meals, beverages, and
dietary supplements consumption on L-T4 pharmacokinetics and pharmacodynamics, to identify the
most evident interactions, and to perform the recommendations for safe co-administering of L-T4
and food. A total of 121 studies were identified following a systematic literature search adhering to
PRISMA guidelines. After full-text evaluation, 63 studies were included. The results proved that L-T4
ingestion in the morning and at bedtime are equally effective, and also that the co-administration of
L -T4 with food depends on the drug formulation. We found limited evidence for L -T4 interactions
with coffee, soy products, fiber, calcium or iron supplements, and enteral nutrition but interest-





 ingly they all resulted in decreased L-T4 absorption. The altered L-T4 efficacy when ingested with
Citation: Wiesner, A.; Gajewska, D.;
milk, juices, papaya, aluminium-containing preparations, and chromium supplements, as well as
Paśko, P. Levothyroxine Interactions observed enhancement effect of vitamin C on L-T4 absorption, shall be further investigated in larger,
with Food and Dietary Supplements– well-designed studies. Novel formulations are likely to solve the problem of coffee, calcium and
A Systematic Review. Pharmaceuticals iron induced malabsorption of L-T4. Maintaining a proper time interval between L-T4 and food
2021, 14, 206. https://doi.org/ intake, especially for coffee and calcium, or iron supplements, provides another effective method of
10.3390/ph14030206 eliminating such interactions.

Academic Editors: Paolo Arosio and Keywords: levothyroxine; food; interaction; coffee; fiber; soy
Félix Carvalho

Received: 29 December 2020

Accepted: 25 February 2021
1. Introduction
Published: 2 March 2021
Levothyroxine (L-thyroxine, L-T4) is a drug of choice for treating primary hypothy-
Publisher’s Note: MDPI stays neutral
roidism, which in developing countries generally occurs due to Hashimoto thyroiditis,
with regard to jurisdictional claims in
thyroidectomy, or iodine deficiency [1]. In 2020, L-T4 was the third most often prescribed
published maps and institutional affil- drug in the USA [2]. Interactions between L-T4 and food may affect the safety and efficacy
iations. of the treatment but are still widely underestimated by patients and health care profession-
als. McMillan et al. [3] surveyed hypothyroid patients to determine the factors affecting
L -T4 therapy. Out of 925 participants, 51.8% used dietary supplements known to interact
with L-T4, especially calcium (47.5%) and iron (11.9%), whereas 68% reported frequent
Copyright: © 2021 by the authors.
(more than twice a week) intake of food and beverages rich in fiber (bran flakes, fiber bars,
Licensee MDPI, Basel, Switzerland.
fiber drinks, or broccoli florets), iodine (dried seaweed, cranberries, plain yogurt, cod), or
This article is an open access article
soy. The disturbing findings were that 20% of patients took L-T4 together with breakfast,
distributed under the terms and lunch, or dinner, and 21.5% administered the drug less than 30 min before the meal. Simul-
conditions of the Creative Commons taneously, 124 patients (13.4%) experienced difficulties in controlling their hypothyroid
Attribution (CC BY) license (https:// symptoms. Thus, the authors suggest that L-T4 interactions with food, beverages, and
creativecommons.org/licenses/by/ dietary supplements, consumed by the participants, can, at least partly, explain these facts.
4.0/). The study performed by Michel et al. [4] also revealed the patients’ inadequate knowledge

Pharmaceuticals 2021, 14, 206. https://doi.org/10.3390/ph14030206 https://www.mdpi.com/journal/pharmaceuticals

Pharmaceuticals 2021, 14, 206 2 of 20

on L-T4 proper administration schedules. Forty five patients, treated with L-T4, completed
a telephone survey. Out of 21 participants, 80% ingested calcium supplements within 4 h
before, or after taking L-T4, whereas 67% within 1 h. Five patients reported administering
iron or magnesium supplements within less than 1 h from taking L-T4. Only two of all the
participants were advised to separate supplements and L-T4 intake.
This review is aimed to investigate the potential effects of meals, beverages, and di-
etary supplements consumption, as well as dosing regimen, on L-T4 pharmacokinetics and
pharmacodynamics and to identify the most probable interactions. Moreover, some safety
recommendations for co-administering L-T4 with food were suggested and performed in
the review. Knowledge of how to avoid interactions may improve not only the efficacy and
safety of L-T4 treatment, but also contributes to a better patient’s compliance.

2. Results and Discussion

2.1. Eligible Studies
As presented in Figure 1, a total of 121 articles were initially identified. After removing
12 duplicates, titles and abstracts of 109 studies were screened independently by two
researchers (AW and PP), and 22 articles were excluded as not meeting the inclusion
criteria, thus leaving 87 full-text articles that were assessed for eligibility by the same
reviewers, resulting in a further 24 articles being removed according to the exclusion
criteria (19 review papers, two not written in English and three in vitro studies). Finally,
a total of 63 studies were included in the qualitative synthesis.

2.2. Aspects of Levothyroxine Pharmacokinetics

L -T4 is absorbed in the small intestine, more precisely in jejunum and ileum, and
to a small extent also in the stomach [5]. In patients with short bowel syndrome L -T4
absorption may be reduced due to increased intestinal passage [6].
Pharmacokinetic parameters of L-T4 differ in euthyroid and hypothyroid subjects.
In patients with hypothyroidism, time to achieve Cmax (tmax ) delays from 2 h to 3 h, the
volume of distribution decreases from 14.7 L to 11.6 L, and the bioavailability can be higher
than standard 60–80% [6–8].
Concomitant gastrointestinal diseases, such as celiac disease, H. pylori infection, lactose
intolerance, inflammatory bowel disease, and even parasitic infestation (G. lamblia), etc.
may cause L-T4 malabsorption [5,6].
Increased gastric pH is known to alter L-T4 absorption as well [9]. Several studies
confirmed that patients with impaired gastric acid secretion, either due to the disease, or
using pomp proton inhibitors (PPI), may need higher L-T4 doses to achieve the desired TSH
level [10,11]. The interaction is clinically significant for chronic PPIs administration [12].
Pantoprazole and esomeprazole do not seem to alter pharmacokinetic parameters of L-T4,
though the evidence is insufficient to prove its safety [13,14].
Apart from the tablets (Euthyrox, Levoxyl, Synthroid), L-T4 is also available in other
forms such as soft gel capsules (Tirosint), oral liquid (Tirosint-SOL), and powder to prepare
an intravenous solution (Synthroid). Changing the drug formulation may solve the prob-
lem of L-T4 malabsorption caused by the diseases, increased gastric pH, and drug-food
interaction related factors as well.
Liquid L-T4 is absorbed faster than its solid form [15], it was also found to be less
dependable on gastric pH and conditions causing malabsorption [9,16]. Liquid L-T4 lowers
TSH levels more effectively in comparison to the tablets with the same dose, both in
patients with and without malabsorption [16–18]. Switching from the tablets to the oral
liquid formulation has improved L-T4 treatment efficacy in 24 patients ingesting PPI [19]
and 11 ingesting other interfering drugs [20].
L-T4 in soft gel capsules dissolves better in increased pH [21] as well. This formulation,
when compared to the tablets, can improve TSH levels both in patients with gastric diseases
(H. pylori infection, chronic gastritis, etc.) and with no proven malabsorption [22,23].
Pharmaceuticals 2021,2021,
Pharmaceuticals 14, x14,
FOR206PEER REVIEW 3 of 20 3 of 20

Figure 1.
Figure PRISMA flowchart.
1. PRISMA flowchart.

2.3. Schedules of Levothyroxine Administration

2.2. Aspects of Levothyroxine Pharmacokinetics
Previously recommended administration of L-T4 preparations included taking the
L-T4 is absorbed in the small intestine, more precisely in jejunum and ileum, and to
drug upon waking up, due to circadian variability in TSH levels, namely higher level in the
a small
morningextent
[24].also in the stomach
However, [5]. Inhave
recent studies patients withthat
indicated short bowel Lsyndrome
ingesting L-T4 absorp-
-T4 in the evening
tion
maymaybe be reduced
an equally due toregimen.
effective increased In aintestinal
randomized passage
study [6].
conducted on 84 patients, Ske-
linPharmacokinetic
et al. [25] compared parameters of Ltiming
three different -T4 differ in euthyroid
regimens and hypothyroid
for L-T4 administration: subjects.
(1) 30 min In
before breakfast, (2) 1 h before lunch, and (3) at bedtime, more than 2 h after
patients with hypothyroidism, time to achieve Cmax (tmax) delays from 2 h to 3 h, the volume dinner. TSH,
of free T4 (fT4), and
distribution free T3from
decreases (fT3) levels
14.7 Lwere measured
to 11.6 at the
L, and the beginning andcan
bioavailability after
be8 higher
weeks than
of each regimen.
standard 60–80% [6–8]. The results were comparable with baseline in all 3 groups. The authors
concluded that different timing regimens for L-T4 are equally effective. Similar results were
Concomitant gastrointestinal diseases, such as celiac disease, H. pylori infection, lac-
obtained in many other studies [26–30]. The decrease in bowel movements at night, and
tose intolerance, inflammatory bowel disease, and even parasitic infestation (G. lamblia),
the resulting increase in intestinal absorption of L-T4 may be a possible explanation of the
etc.described
may cause L-T4 malabsorption
observations [31]. A recent [5,6].
meta-analysis [32] confirmed, that L-T4 ingestion at
Increased
bedtime gastric pH
is as effective is one
as the known
beforetobreakfast.
alter L-T4 Anabsorption as well [9].may
evening administration Several studies
reduce
confirmed
the risk ofthat patients
drug-food with impaired
interactions gastric
and enhance theacid secretion,
patient’s eitherwith
compliance duetheto treatment.
the disease, or
using pomp proton inhibitors (PPI), may need higher L-T4 doses to achieve the desired
TSH level [10,11]. The interaction is clinically significant for chronic PPIs administration
[12]. Pantoprazole and esomeprazole do not seem to alter pharmacokinetic parameters of
L-T4, though the evidence is insufficient to prove its safety [13,14].
Pharmaceuticals 2021, 14, 206 4 of 20

2.4. Impact of Food Intake on Pharmacokinetics and Pharmacodynamics of Levothyroxine

L -T4 absorption and bioavailability, with regard to the food, depend on the drug
formulation (tablets, an oral liquid form, or soft gel capsules). In some countries tablets are
the only available L-T4 formulation.

2.4.1. Tablets
L -T4 is absorbed from the tablet within 20–30 min after ingestion; it takes about 3 h
to complete the absorption process [7]. In the presence of food, tmax delays, and the peak
value of L-T4 absorption decreases [6,33], similarly to drug bioavailability, from 15 to as
much as 40%, depending on the study [34,35]. Lamson et al. [35] administered a single
dose of 600 µg L-T4 to 48 euthyroid volunteers, either at breakfast, or 30 min before it,
with 35 day washing period between both administration regimens. Breakfast consisted
of eggs, bacon, toast, hash brown potatoes, milk, providing 950 kcal, 16% protein, 26%
carbohydrate, and 58% fat. The authors observed significantly decreased AUC0-48h (by
38–40%) and Cmax (by 40–49%) in participants taking L-T4 with food [35].
The concomitant ingestion of L-T4 with food affects not only drug pharmacokinetics
but also the efficacy of the treatment (measured by the changes in TSH, fT3, and fT4 levels).
Seechurn et al. [36] evaluated the effect of changing L-T4 administration to 45–60 min
before breakfast on elevated serum TSH levels. In all 10 patients who started to ingest
L -T4 (in a medium dose of 175 µg) while fasting, TSH levels decreased significantly (by
40–96%), while the increase in fT4 levels was observed after 2 months. The results of this
study, along with several other [33,37] support the recommendation to postpone food by at
least 30–60 min after L-T4 tablet ingestion [5,6].
Perez et al. [38] conducted a randomized study on 42 hypothyroid patients, to compare
L -T4 administration (in a daily dose of 98.3 ± 35.2 µg) while fasting and with breakfast.
Patients consumed mostly: coffee (88.1%), white sugar (81.0%), whole milk (71.4%), white
bread (69.0%), margarine (59.5%), cheese (23.8%), savoury biscuits (16.7%), non-fat milk
(11.9%), whole wheat bread (9.5%), and fruits (9.5%). A standard breakfast provided
approximately 162-381 kcal and consisted of 57.5% carbohydrates, 28.4% fat, 14.1% protein,
and 254.1 ± 62.6 mg calcium. The fiber consumption was insignificant. TSH levels were
measured at the beginning of the study and on 45, 90, 135, and 180th day. Administering
L -T4 tablets with breakfast resulted in significantly higher TSH levels (2.89 ± 2.82 vs.
1.9 ± 1.76 mU/L). However, Perez et al. [38] concluded that the intake of L-T4 tablets with
food can be safe and well-tolerated alternative for non-adherent patients, though it requires
more frequent monitoring of TSH levels. On the contrary, patients in whom even small
variations of TSH level are dangerous (i.e. pregnant women, patients with cardiac disease,
or thyroid cancer) should avoid taking L-T4 with meals [38].

2.4.2. Liquid Form

In vitro studies proved the stability of liquid L-T4 formulation in beverages such as
milk, tea, coffee, coffee with milk, and orange juice [39]. The liquid form has also a faster
onset of absorption, compared to tablets (AUC0-2h (ng*h/mL): 99.1 ± 22.7 vs. 68.4 ± 32.8;
tmax (h): 1.96 ± 1.07 vs. 2.25 ± 0.99). Greater early exposure and faster time to maximal
concentration can minimize the risk of drug-food interactions [15].
Marina et al. [40] examined fT4 levels in 14 patients taking 200 µg of oral liquid L-T4;
seven of them administered L-T4 while fasting, and seven with breakfast consisting of six
cookies (132 kcal, 9.1% fat, 76.9% carbohydrate, 7.7% protein, 3.8% fiber) and one cup of
espresso or cappuccino, both with 5 g of sucrose. The results were comparable in both
groups. In another study on 59 hypothyroid patients, Morelli et al. [41] found no significant
differences in the TSH level when administering liquid L-T4 with breakfast, or 10 and
30 min before (1.52 ± 0.73 mU/L, 1.46 ± 0.81 mU/L, and 1.25 ± 0.7 mU/L respectively).
Cappelli et al. [42] conducted a randomized, double-blind, placebo-controlled trial
on 77 hypothyroid patients. They assessed whether the patient’s usual breakfast (mixed
with tea, coffee, milk, cappuccino, orange juice, etc.) may influence liquid L-T4 absorption.
Pharmaceuticals 2021, 14, 206 5 of 20

Serum TSH, fT4, and fT3 levels were comparable in patients administering liquid L-T4
formulation (in a median dose of 75 µg) with breakfast, and 30 min before. The authors
concluded that liquid L-T4 can be ingested directly with the meal. Pirola et al. [43] got
similar results for the same median dose of L-T4 (75 µg), on an extensive set of 761 patients.
A possibility to administer liquid L-T4 with food may have a positive influence on
patient compliance and well-being [44]. Among 102 patients, dissatisfied with their therapy
with L-T4 tablets (in a mean dose of 88 ± 34.7 µg), taken before the meal, 66.6% reported
improvement in the quality of life and better adherence after switching to liquid L-T4
ingested with breakfast [45]. Treatment with liquid l L-T4 formulation can be considered
also in patients who are willing to keep their daily habits [46].

2.4.3. Soft Gel Capsule

We found only one study [47] investigating how meals affect absorption of L-T4 in a
soft gel capsule formulation. In a group of 60 euthyroid patients taking oral liquid L-T4
with breakfast, the drug was switched to the soft gel capsule form, without a change in
a mean dose (106.25 ± 24.28 µg/day). Each patient maintained his dietary habits; their
breakfast commonly included biscuits, yogurt, fibers, milk, coffee, tea, and orange juice.
Cappelli et al. [47] measured TSH, fT4, and fT3 levels in all the patients at the beginning
and after 6 months of treatment with a new formulation. No significant difference in the
TSH level was found; fT4 and fT3 levels were slightly but considerably lower in patients
treated with L-T4 in soft gel capsule form (by an average 7% both). The authors concluded
that soft gel formulation can be taken during breakfast. Nevertheless, it is oral liquid form
rather than soft gel capsules that is preferred for maintaining a stable fT4 and fT3 levels in
patients with thyroid cancer or cardiomyopathy [47].

2.5. Levothyroxine–Fiber Interaction

To deal with hypothyroidism symptoms, like overweight, obesity, or constipation
patients often introduce a fiber-enriched diet, or administer dietary fiber supplements,
without consulting their doctor. The diet type may, however, significantly influence the
bioavailability of L-T4.
L -T4 non-specifically adsorbs to the fiber, what leads to the malabsorption of the
drug [48]. Additionally, products that contain insoluble dietary fiber intensify bowel
movements, and in consequence, intestinal absorption of L-T4 could be altered [33].
Liel et al. [49] described cases of 13 hypothyroid patients in whom the ingestion
of fiber-enriched products (e.g. whole wheat bread, bran, granola, psyllium) led to a
significant decrease in the efficacy of L-T4 tablets (in dosage range 50–470 µg/day). The
authors suggested monitoring TSH levels in patients following diet modifications and
increasing the dose of L-T4 when necessary.
Chiu et al. [50] assessed the effect of pharmacological fiber supplements on L-T4
absorption in 8 volunteers, who ingested 600 µg of L-T4 tablets alone or together with
3.4 g psyllium. The L-T4 absorption was expressed as a percentage of the administered dose.
The observed decrease in drug absorption, due to the simultaneous ingestion of psyllium,
reached only 9% (89% vs. 80%). The authors considered this result as clinically insignificant
and concluded the psyllium fiber not to be likely to alter L-T4 tablets bioavailability.

2.6. Levothyroxine-Soy Products Interaction

In the recent systematic review by Otun et al. [51] it was concluded that soy supple-
mentation had no effect on thyroid hormones (T3 and T4), though it slightly increased
TSH level (with unknown clinical significance). Here, the presented data show possible
interaction of soy active components: soy protein and soy isoflavones, with L-T4 treatment.
Since the mid-1960s, several reports suggested that feeding soy-based formulas to infants
with congenital hypothyroidism may lead to malabsorption of L-T4 tablets, and increased
TSH levels [52–55]. Conrad et al. [56] confirmed the negative influence of soy isoflavones
on the L-T4 treatment efficacy (measured by TSH level) for a group of 78 infants with L-T4
Pharmaceuticals 2021, 14, 206 6 of 20

congenital hypothyroidism. The authors emphasized the necessity for controlling the levels
of thyroid hormones to adjust L-T4 doses in patients receiving soy formulas.
Bell et al. [57] reported a case of a 45-year-old woman after thyroidectomy—treated
with 200 µg of L-T4 in tablets—who regularly ingested a soy protein-containing cocktail
together with L-T4. In consequence, her fT4 and TSH levels became elevated; she also
required higher L-T4 doses to achieve euthyroidism. Free T4 and TSH levels became
normalized after advising the patient to separate the soy protein and L-T4 intake. The
observed interaction occurred due to the adsorption of L-T4 on the surface of soy protein.
Soy isoflavones-containing supplements are widely used by women to relieve
menopausal symptoms. Persiani et al. [58] conducted a randomized controlled trial on
12 post-menopausal women with hypothyroidism. They investigated the effect of soy
isoflavones on bioavailability of L -T4 tablets. Patients received a supplement containing
60 mg of soy isoflavones (>19% of genistein and daidzein) with, or 6 h after, L -T4 in a
daily dosage that ranged between 25–125 µg. The authors found no significant changes
in L -T4 pharmacokinetics when administered with soy isoflavones.

2.7. Levothyroxine–Milk Interaction

We found only one study where the influence of milk on L -T4 absorption was in-
vestigated. Chon et al. [59] administered 1000 µg of L -T4 tablets alone or together with
355 mL of 2% cow milk (containing 450 mg of calcium) to 10 healthy patients. Then they
measured peak serum TT4 concentrations and AUC, both parameters were significantly
lower in patients ingesting L-T4 with cow milk—by 7.8% and 8%, respectively. The results
of this research cannot be extrapolated to plant-based milk alternatives (such as almond,
oat, coconut, or rice milk), due to different concentrations of protein and calcium. The
separation time needed to avoid possible L-T4 and milk interaction is still unknown.

2.8. Levothyroxine–Coffee Interaction

Several studies on patients with hypothyroidism revealed that coffee could decrease
the efficacy and safety of L-T4 treatment. The proposed mechanism for this interaction
was the sequestration of L-T4 by coffee and in consequence, altered intestinal absorption
of the drug [60]. Benvenga et al. [61] investigated the influence of espresso (without milk
or sugar) when co-administered with L-T4. Six hypothyroid and nine healthy women
were administered two 100 µg L-T4 tablets swallowed with (1) coffee, (2) water, or (3)
water followed by coffee 60 min later. Th authors measured average and peak incremental
rise of serum T4 concentrations and time to reach maximal serum level. Compared to
water, coffee significantly lowered the incremental rise of serum T4 level, both average (by
36% in thyroid patients and 29% in volunteers) and peak (by 30% and 19%, respectively).
It also significantly delayed time to reach maximal serum level (by 38 and 43 min). As no
significant difference was found between groups (2) and (3), it was suggested that 1h break
between coffee and L-T4 is enough to prevent the interaction. Additionally, an in vitro
study found coffee to be 2-times weaker than other agents, such as antacids and fiber,
known to interfere with L-T4 absorption. Sindoni et al. [62] presented cases of 6 patients
in whom serum TSH level failed to be normalized or suppressed. All patients, within
1.6–2.2 µg/kg daily dosage range, declared to take L-T4 tablets together with, or shortly
before, their morning espresso or barley coffee. Advising patients to separate coffee and
L -T4 by 1 h, helped them to achieve euthyroidism.
Recently, the interaction of L-T4 with American coffee (drip coffee) was also reported.
W˛egrzyn [63] described a case of a 52-year-old woman who developed clinical signs of
hypothyroidism after taking in the morning 175 µg of L-T4 in tablets, with a cup of drip
coffee. The patient was advised to postpone drinking coffee by 1h after taking L-T4. Her
TSH levels normalized in 6 weeks (from 8.27 to 0.24 mU/L).
The above cases refer to L-T4 in tablets. Recent studies suggest that coffee-induced
malabsorption of L-T4 can be reduced by replacing the tablets with soft gel capsules or
liquid form.
Pharmaceuticals 2021, 14, 206 7 of 20

Vita et al. [64] assessed a 6-month study on eight patients with coffee-associated L-T4
malabsorption. Participants were switched from the tablet form to the soft gel capsule
without a change in L-T4 daily dose; the dosage ranged from 1.6 to 2.8 µg/kg. For the first
3 months, patients swallowed the capsule with water, and had their coffee 1 h later. On days
91–180 coffee was administered less than 5 min after L-T4. TSH levels, measured at the end
of each part of the study, were comparable, regardless of the time between administering
coffee and L -T4 soft gel capsules.
Cappelli et al. [65] obtained similar results for the liquid form of L-T4. The authors
identified 54 patients taking oral liquid L-T4 (mean dosage: 73.15 ± 17.41 µg/day) with
breakfast and morning coffee. Following evaluation of TSH, fT4, and fT3, they advised
patients to consume L-T4 at least 30 min before breakfast. The tests were repeated 3 and
6 month later, and no significant differences in thyroid hormones concentrations were found.

2.9. Levothyroxine-Fruit Interaction

2.9.1. Fruit Juices
Different categories of transporters contribute to carrying L-T4 from the small intes-
tine to the bloodstream, i.e. the organic anion-transporting polypeptide (OATP) family
(such as OATP1A2, OATP1B1, OATP1C1, etc.), the monocarboxylate transporter (MCT)
family or NTCP (sodium-taurocholate co-transporting polypeptide) transporters [5,66].
Active ingredients of juices—especially grapefruit, orange, and apple juice—may block the
transporters [67,68].
Lilja et. al. [69] reported a case of a 36-year-old hypothyroid woman, successfully
treated with L-T4 (100 µg daily). Her TSH level became elevated (63.7 mU/L) and fT4
concentration decreased (6.4 pmol/L) after marked consumption of grapefruit juice. In-
creasing the L-T4 dose to 150 µg was ineffective. After advising the patient to drink less
grapefruit juice, TSH and fT4 levels returned to the normal range (TSH—0.291 mU/L,
fT4—17 pmol/L).
Based on this case, in a randomized study, Lilja et al. [69] assessed the influence of
grapefruit juice on the pharmacokinetics of L-T4. 10 healthy volunteers were administered
200 mL of grapefruit juice three times a day for 2 days. On day 3, they ingested grapefruit
juice 1 h before, together with, and 1 h after a single 600 µg dose of L-T4. Grapefruit juice
reduced L-T4 AUC only by 9% and slightly decreased Cmax (by 11%). TSH levels measured
up to 24 h were comparable to the control group. The authors concluded that the relevance of
the grapefruit juice- L-T4 interaction seems to be small. Yet, the lack of significant interaction
observed in that study may be due to conducting it on healthy subjects. Meyer et al. [70]
found that thyroid hormones upregulate OATP2B1 expression, thus, hypothyroidism may
influence juice- L -T4 interaction.
Recently Tesic et al. [71] presented a case of a 31-year-old woman, unsuccessfully
treated with high doses of L-T4 alone (200–700 µg a day) or in combination with liothy-
ronine (Novothyral 100, 3 times a day). The patient reported taking L-T4 tablets on an
empty stomach but often with juice or mint tea. Few days after advising the patient to
administer L-T4 with water, TSH level normalized (from initial > 100 to 9.4 mU/L), and
fT3 level increased (from 5.9 to 10.8 pmol/L), as well as fT4 level (from undetectable to
7.4 pmol/L). The authors suggested that juice or mint tea interfered with L-T4 absorption
in that case.
Given limited and contrary data, L-T4 -treated patients should not be discouraged
from rational fruit juice consumption.

2.9.2. Papaya
A sudden change in a diet may impair the effectiveness of L-T4 therapy. Deiana et al. [72]
reported a case of a 37-year-old patient after thyroidectomy, euthyroid on L-T4 dose of
1.6 µg/kg, with TSH levels from 1.2 to 1.9 mU/L. The patient had his check of thyroid
function 7 days after a 2- week trip to the Caribbean country. The doctor documented an
unexpected increase in the TSH level (25 mU/L). The patient reported the intake of large
Pharmaceuticals 2021, 14, 206 8 of 20

amounts of papaya (5–6 fruit per day) during his vacations. After 45 days without ingesting
papaya, serum TSH concentration returned to the reference range. To confirm the interaction
between L-T4 and papaya, the patient was asked to eat the same amount of papaya, as he did
during vacations. The researchers measured serum levels of TSH, fT4, and fT3 before and
after 7 and 14 days of excessive fruit ingestion. They found no effect in the first week but after
14 days observed an increase in TSH level (from 0.8 to 15 mU/L) and reduction of fT4 and
fT3. The patient returned to the euthyroid state after discontinuing papaya intake.
The authors discussed possible mechanisms for interaction between L-T4 and papaya.
The active principle of the fruit - papain, reduces the secretion of gastric acid (up to 48 h)
and increased gastric pH is associated with lower L-T4 absorption. Other fruit ingredients
(i.e., terpenoids, saponins, alkaloids, and flavonoids) have cytoprotective and antiulcer
properties, and can also reduce L-T4 absorption. Furthermore, papaya contains fiber, which
can bind L-T4 in the intestine at such extensive intake of the fruits [72].

2.10. Interaction of Levothyroxine with Essential and Trace Elements

Di- and trivalent elements, especially calcium and iron, may decrease L-T4 bioavail-
ability, making treatment less effective [73,74]. The proposed mechanisms that lead to
increased elimination of L-T4 involve unspecific adsorption and creating insoluble com-
plexes in the intestine [11,75]. Thus, health care professionals should discuss with their
patients the adverse effects of self-supplementation likely to occur.

2.10.1. Calcium
The effect of L-T4 treatment on bone mineral density is still an open question [76] but
patients with hypothyroidism, especially postmenopausal women, may often use calcium
supplements to prevent L-T4 -induced osteoporosis [77,78]. In a cohort study on 20 patients
with hypothyroidism, Singh et al. [77] indicated that calcium carbonate may reduce L-T4
absorption. After 3-month co-administering 1200 mg/day of elemental calcium with L-T4
in a dose of 1.0 µg/kg or greater, the patients’ fT4 levels were significantly reduced, while
20% of patients had their TSH level higher than standard. Thyroid hormones concentrations
normalized after calcium carbonate discontinuation. A year later Singh et al. [79] confirmed
those results for 2000 mg daily dose of calcium, acutely administered with 1000 µg of L-T4
in tablets. Interactions between calcium carbonate and L-T4 were also reported in several
case studies [80–83].
Irving et al. [11] performed a large observational study on patients, who were prescribed
L-T4 tablets at least three times in 6 months. Out of all participants, 450 co-administered
calcium preparations, and 429 iron supplements. The authors analyzed TSH measurements
for 1 year from starting the supplementation. Taking calcium with L-T4 resulted in a significant
increase in serum TSH (up to over 5 mU/L) in 4.4% of patients. Similar results were obtained
for the iron group where 7.5% of the participants had increased TSH levels. Researchers
concluded that calcium and iron supplements can decrease L-T4 absorption.
Other calcium preparations were also examined for the potential interaction with
L -T4. Diskin et al. [84] compared TSH levels in 65 patients taking L -T4, in a mean dose
between 95–98 µg/day, with different phosphate binders. Researchers found that adminis-
tering calcium carbonate, but not calcium acetate, resulted in a significantly higher TSH
level (23.8 ± 19.5 mU/L). Calcium acetate interference with L-T4 absorption was denied.
Zamfirescu et al. [85] made different conclusions after comparing the effect of calcium
formulations—acetate, citrate, and carbonate, each in a dose containing 500 mg of elemen-
tal calcium—on the absorption of L-T4 tablets in a dose of 1000 µg. Co-administration
of each of the three calcium preparations in eight healthy adults resulted in a significant
reduction (20 to 25%) of L-T4 absorption, compared to L-T4 alone. Researchers emphasized
that patients should take L-T4 and all the examined calcium formulations well-separated
in time.
Morini et al. [86] performed a cohort study on a group of 50 postmenopausal, hypothy-
roid women. They confirmed the malabsorption of L-T4 tablets (in a daily median dose
Pharmaceuticals 2021, 14, 206 9 of 20

of 1.47 µg/kg) when co-administered with calcium supplements containing 600–1000 mg

elemental calcium/day. The researchers observed an increase not only in the TSH level but
also in blood pressure, total cholesterolemia, and fasting glycemia. The effects occurred
solely for calcium supplements administered within 2 h after L-T4.
Interaction with calcium can be avoided by switching from L-T4 in tablets to oral
liquid form. Benvenga et al. [87] studied 12 hypothyroid patients on daily 1000 mg of
calcium. Calcium carbonate was administered 2–4 h after two different L-T4 formulations
in a median daily dose of 1.7 µg/kg. The first test, after 6–8 weeks, revealed significantly
lower TSH levels with the liquid formulation compared to tablets, namely 2.15 ± 1.4 mU/L
vs. 8.74 ± 7.2 mU/L. The effect lasted after a 25-week follow-up. Researchers concluded
that oral liquid L-T4 is resistant to sequestration by calcium.
Interaction between calcium compounds and L-T4 is well documented. Still, patients’
knowledge on the subject remains insufficient. Mazokopakis et al. [88] surveyed 153 pa-
tients and revealed that only 8.4% of them took the calcium carbonate separated at least 4 h
from L-T4.

2.10.2. Iron
Phenolic, carboxylate, and amine functional groups on L-T4 facilitate the formation
of insoluble or sparingly soluble complexes with ferrous salts, and this process may alter
drug absorption.
Campbell et al. [89] observed reduced efficacy of L-T4 (in dosage range 75–150 µg)
when administered with 300 mg of ferrous sulfate. After 12 weeks of study, the mean level
of serum TSH increased from 1.6 ± 0.4 to 5.4 ± 2.8 mU/L in 11 out of 14 patients (79%).
Clinical symptoms of hypothyroidism occurred in nine participants. L-T4 malabsorption
due to co-administering ferrous sulfate was also described in several case reports [90], [91].
Shakir et al. [90] suggested that such interaction can occur despite maintaining the 4–6 h
interval between L-T4 and ferrous preparation.
Leger et al. [92] reported the case of a 60-year-old woman, successfully treated with
L -T4, who became hypothyroid after starting a daily intake of ferrous fumarate. She
experienced elevated TSH level (243 mU/L, reference: 0.32–5.00 mU/L), and decreased T4
serum levels (<0.52 pmol/L, reference: 11.0–23.0 pmol/L). Her thyroid function normalized
after 2 months of discontinuing iron supplementation.
In a recent cohort study, Atruktsang et al. [93] investigated the time to achieve euthy-
roidism in 605 patients treated with L-T4 in the initial dose of 1.6 µg/kg. 97 participants
(16%) needed three or more dose adjustments and were classified as a prolonged dose
adjustment (PDA+ group). Compared with PDA-, PDA+ group used ferrous supple-
ments more often (1.8% in PDA- vs. 6.2% in PDA+). The researchers concluded that iron
supplementation could be associated with prolonged L-T4 dose adjustment.
Similar to calcium, the use of an oral liquid form may correct L-T4 malabsorption
caused by ferrous preparations. On a group of 8 hypothyroid subjects, Benvenga et al. [87]
analysed the possibility of L-T4 interaction with iron. Patients were administered 329.7 mg
of ferrous sulfate, 2–4 h after the ingestion of different L-T4 formulations in a median daily
dose of 1.7 µg/kg. The authors observed a significant decrease in TSH level in patients
taking oral liquid L-T4, compared to tablets (1.68 ± 0.9 mU/L vs. 8.74 ± 7.2 mU/L).

2.10.3. Aluminium
Aluminium-containing preparations are available without prescription as antacids.
Several case studies reported L-T4 malabsorption due to concomitant use of aluminium
hydroxide [94,95]. Liel et al. [75] studied five hypothyroid subjects balanced on L-T4.
Patients were administered two aluminium hydroxide-containing gel tablets 4 times a day
for 2–4 weeks. A significant increase in serum TSH, specifically from 2.62 to 7.19 mU/L,
was observed during periods of aluminium hydroxide ingestion.
Pharmaceuticals 2021, 14, 206 10 of 20

2.10.4. Chromium
Although the effectiveness and safety of chromium picolinate supplementation in
overweight and obese people are controversial [96,97], patients with thyroid diseases may
use chromium supplements to control body weight.
We found only one study on seven healthy volunteers, testing the effect of concomitant
use of L-T4 (1000 µg) and chromium picolinate (1 mg). It was revealed that chromium
supplementation decreases L-T4 bioavailability by 17% [98].
Detailed recommendations on chromium and L-T4 intake cannot be made due to
the lack of further research. Nevertheless, following L-T4 interactions with other di- and
trivalent metals, patients shall be advised to delay chromium preparations use to 2–4 h
after L-T4 ingestion.

2.11. Levothyroxine—Vitamin C Interaction

Increased pH in the stomach affects the absorption of L-T4, thus, it was investigated
whether vitamin C, an agent known to lower gastric pH, could enhance L-T4 absorption.
The data, although limited, look promising.
Jubiz et al. [99] conducted the study on 31 patients with hypothyroidism and gastritis.
Participants swallowed L-T4 tablets, in a median daily dose of 100 µg, with 120 mL of water
containing, or not, 500 mg vitamin C. Researchers measured serum levels of fT4 and TSH
at the end of 2, 4, and 6 months. TSH level decreased significantly in all patients (with the
average of 69.2%) and normalized in 54.8% of them (11.1 mU/L in a control vs. 4.2 mU/L
in a vitamin C group). Free T3 and fT4 levels increased significantly in almost all patients.
Antunez et al. [100] achieved similar results in the study conducted on 28 patients with
elevated TSH levels, despite being on the L-T4 dose higher than 1.70 µg/kg. Researchers
asked patients to take L-T4 tablets with 1 g of vitamin C (in effervescent tablets, dissolved
in 200 mL of tap water) for 6–8 weeks. A significant decrease in serum TSH level (from
9.01 ± 5.51 mU/L to 2.27 ± 1.61 mU/L) was observed afterwards.

2.12. Levothyroxine—Enteral Nutrition Interaction

Reis et al. [101] conducted a multicenter study in Intensive Care Units of seven teaching
hospitals in Brazil to assess the prevalence of drug-enteral nutrition (EN) interactions. They
considered L-T4—EN interaction as clinically significant and one of the most frequent.
In a former study, Dickerson et al. [102] examined 13 patients with hypothyroidism.
Participants received EN with L-T4 at the same dose as before the hospitalization for
20 ± 5 days. Thyroid function tests (TFTs) were performed before co-administration and
then approximately once a week. Eight patients developed hypothyroidism: subclinical
(TSH —6–10 mU/L, normal fT4) or overt (TSH >10 mU/L, low fT4). Researchers recom-
mended to perform TFTs once a week in patients receiving continuous EN and L-T4.
Manessi et al. [103] discovered that L -T4, when combined with EN, may adsorb to
enteral feeding tubes. It was proposed as the reason for the observed decrease in drug
efficacy. However, Wohlt et al. [104] stated that this mechanism is probably clinically
insignificant, and suggested that altered L -T4 absorption is rather due to the ingestion
together with food.
Pirola et al. [105] compared the effect of administering different formulations of L-T4,
in a daily dose of 1.6 µg/kg, via an enteral feeding tube. They conducted a study on
20 euthyroid patients, one day after surgery. Nurses stopped EN for 30 min before and after
administering crushed L-T4 tablets; the liquid form was placed into a feeding tube with
continuous enteral nutrition. Researchers measured thyroid hormones profile before and
after L-T4 treatment with both formulations. The results were comparable, so the authors
concluded that EN does not affect liquid L-T4 absorption. In the survey, nurses stated also
that liquid formulation is easier to prepare and administer.
In Table 1, we summarized data from the most relevant works, including number
of patients, their health state, L-T4 dose and formulation, type of investigated food, and
effects observed in each study.
Pharmaceuticals 2021, 14, 206 11 of 20

Table 1. Summary of data from the most relevant studies investigating the influence of food on levothyroxine pharmacokinetics and pharmacodynamics.

L-T4
Study Participants L-T4 Dose (µg/Day) Type of Food Observed Effect
Formulation
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
not
Morelli et al. [41] 59, hypothyroid liquid form patient’s usual breakfast no significant changes in TSH levels
specified
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
no significant changes in TSH levels, ↓ fT4 and fT3 levels (by
Cappelli et al. [47] 60, euthyroid 106 ± 24 soft gel capsules patient’s usual breakfast
7% both)
Not fiber (whole wheat bread, bran,
Liel et al. [49] 13, hypothyroid 50–470 ↑ TSH level (ranging from 7,4 to > 50 mU/L)
specified granola, psyllium)
Chiu et al. [50] 8, healthy 600 Tablets fiber (psyllium) ↓ L-T4 absorption (by 8%)
Not
Fruzza et al. [55] 1, hypothyroid 50 soy-based infant formula ↑ TSH level (216 mU/L), ↓ fT4 level (4.0 µg/dL)
specified
Not
1, hypothyroid 112 soy-based infant formula ↑ TSH level (248 mU/L), ↓ fT4 level (<0.4ng/dL)
specified
Not
Conrad et al. [56] 78, hypothyroid 7.4 per kg soy-based infant formula 62.5% patients with TSH > 10 mU/L after 4 months
specified
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
W˛egrzyn [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
comparable TSH, fT3 and fT4 levels for coffee 30 min. before
Cappelli et al. [65] 54, hypothyroid 73±14 liquid form coffee
and with L-T4
Not
Lilja et al. [69] 1, hypothyroid 100 grapefruit juice ↑ TSH level (63.7 mU/L), ↓ fT4 level (6.4 pmol/L)
specified
Not
10, healthy 600 grapefruit juice ↓ AUC (by 9%), ↓ Cmax (by 11%)
specified
Pharmaceuticals 2021, 14, 206 12 of 20

Table 1. Cont.

L-T4
Study Participants L-T4 Dose (µg/Day) Type of Food Observed Effect
Formulation
↑ TSH level (> 100 mU/L), ↓ fT4 level (5.9 pmol/L),
Tesic et al. [71] 1, hypothyroid 200–700 Tablets juice and mint tea
undetectable fT3 level
1.6 Not
Deiana et al. [72] 1, hypothyroid papaya ↑ TSH level (25 mU/L)
per kg specified
1.6 Not
1, hypothyroid papaya ↑ TSH level (from 0.8 to 15 mU/L), ↓fT3 and fT4 levels
per kg specified
>1 Not
Singh et al. [77] 20, hypothyroid calcium carbonate ↓fT4 level, ↑ TSH level in 20% of patients
per kg specified
↓ L-T4 absorption (from 83.7% to 53.7%), tmax delayed (from
Singh et al. [79] 7, healthy 1000 Tablets calcium carbonate
2 to 4 h)
Not
Schneyer et al. [80] 3, hypothyroid 125–325 calcium carbonate ↑ TSH level (ranging from 7.3 to 13.3 mU/L)
specified
Not
Csako et al. [81] 1, hypothyroid 175–188 calcium carbonate ↑ TSH level (41.4 mU/L)
specified
Not
Butner et al. [82] 1, hypothyroid 150 calcium carbonate ↑ TSH level (21.85 mU/L)
specified
Mazokopakis et al. Not
1, hypothyroid 88 calcium carbonate ↑ TSH level (9.8 mIU/L),↓fT4 level (0.2 ng/dL)
[83] specified
not
Irving et al. [11] 450, hypothyroid Tablets calcium carbonate ↑ TSH level (up to over 5 mU/L) in 4.4% of patients
specified
Not
Diskin et al. [84] 65, hypothyroid 95–98 calcium carbonate ↑ TSH level (23.8 ± 19.5 mU/L)
specified
calcium carbonate, calcium
Zamfirescu et al. [85] 8, healthy 1000 Tablets ↓ L-T4 absorption (by 20–25%)
citrate, calcium acetate
1.47
Morini et al. [86] 50, hypothyroid Tablets calcium supplements ↑ TSH level (3.33 ± 1.93 mU/L)
per kg
1.7 liquid form and ↓ TSH for liquid form vs. tablet (2.15 ± 1,4 mU/L vs.
Benvenga et al. [87] 12, hypothyroid calcium carbonate
per kg tablets 8.74 ± 7.2 mU/L)
Not
Campbell et al. [89] 14, hypothyroid 75-150 ferrous sulfate ↑ TSH level (from 1.6 to 5.4 mU/L)
specified
Not
Shakir et al. [90] 1, hypothyroid 150 ferrous sulfate ↑ TSH level (56 mU/L), ↓ fT4 level (0,48 ng/dL)
specified
not Not
Leger et al. [92] 1, hypothyroid ferrous fumarate ↑ TSH level (243 mU/L), ↓ fT4 level (<0.52 pmol/L)
specified specified
Pharmaceuticals 2021, 14, 206 13 of 20

Table 1. Cont.

L-T4
Study Participants L-T4 Dose (µg/Day) Type of Food Observed Effect
Formulation
not
Irving et al. [11] 429, hypothyroid Tablets iron supplements ↑ TSH level in 7.5% of patients
specified
1.7 liquid form and ↓ TSH for liquid form vs. tablet (1.68 ± 0.9 mU/L vs.
Benvenga et al. [87] 8, hypothyroid ferrous sulfate
per kg tablets 8.74 ± 7.2 mU/L)
not Not
Liel et al. [75] 5, hypothyroid aluminium hydroxide ↑ TSH level (from 2.62 to 7.19 mU/L)
specified specified
John-Kalarickal et al. Not
7, hypothyroid 1000 chromium picolinate ↓ L-T4 bioavailability (by 17%)
[98] specified
Jubiz et al. [99] 31, hypothyroid 100 Tablets vitamin C ↓ TSH level (by 69%), normalized TSH in 54.8% of patients
>1.7
Antunez et al. [100] 28, hypothyroid Tablets vitamin C ↓ TSH level (from 9.01 ± 5.51 mU/L to 2.27±1.61 mU/L)
per kg
not not hypothyroidism subclinical (TSH—6–10 mU/L) or overt
Dickerson et al. [102] 13, hypothyroid enteral nutrition
specified specified (TSH >10 mU/L)
1.6 liquid form and
Pirola et al. [105] 20, euthyroid enteral nutrition comparable thyroid hormones profile for both formulations
per kg crushed tablets
↑ increase ↓ decrease.
Pharmaceuticals 2021, 14, 206 14 of 20

2.13. Limitations of Studies

We recognized several limitations of the presented studies, listed below:
• low level of evidence: most studies are single case reports, case series, cohort studies
(mainly retrospective), clinical studies without control groups (see Figure 1 and Table 2);
• small number of patients in experimental studies: ≤10 participants [36,50,59,61,62,64,
75,79,80,85,87,98];
• presence of older studies: from 1960s [52], 1970s [34], and 1990s [33,49,50,53,54,75,89,90,92];
• unavailable data: in several studies the L-T4 formulation and dose were not men-
tioned (see Table 1) as well as dietary supplement dose [11], and quantitative and/or
qualitative meal composition [33,36,41,42,47];

Table 2. Levothyroxine—food ingredients interactions - recommendations for health care professionals.

Food Interacting Mechanism of Effects of Recommendations for

Sources of Evidence
with L-thyroxine Interaction Interaction Health Professionals

advise to separate fiber and L-T4

Fiber case series [49], intake by 1 h
non-specific adsorption of malabsorption of L-T4,
(whole wheat non-randomized cross-over monitor thyroid parameters more
L -T4 to the fiber impaired efficacy of treatment
bread, bran) study [50] frequently, adjust L-T4 doses when
needed
advise to separate soy protein and
Soy products
case reports [52,53,55,57], case L -T4 intake by 1 h
(soy-protein adsorption of L-T4 on the malabsorption of L-T4,
series [54], retrospective cohort monitor thyroid parameters more
cocktails, soy-based surface of soy protein impaired efficacy of treatment
study [56] frequently, adjust L-T4 doses
infant formulas)
when needed
non-randomized cross-over probable adsorption of L-T4 impaired bioavailability of cannot be made due to the
Cow milk
study [59] on casein L -T4 insufficient evidence
advise to delay coffee intake by 1 h
case report [63], case series
Coffee after L-T4 administration
[61,62], uncontrolled clinical the sequestration of L-T4 malabsorption of L-T4,
(espresso, drip consider changing formulation from
study [65], non-randomized by coffee impaired efficacy of treatment
coffee, barley coffee) tablets to oral liquid
cross-over study [64]
form/gel capsules
Juice
case report [69], randomized cannot be made due to
(grapefruit juice, blocking of OATP malabsorption of L-T4,
clinical trial (against insufficient evidence
orange juice, transporters impaired efficacy of treatment
interaction) [69] advise to avoid excessive intake
apple juice)
cannot be made due to the
Fruit malabsorption of L-T4,
case report [72] unknown insufficient evidence
(papaya) impaired efficacy of treatment
advise to avoid excessive intake
advise to delay intake by 2–4 h after
case reports [81–83], case series
L -T4 administration
[80], retrospective cohort studies unspecific adsorption of L-T4,
Calcium consider changing formulation from
[11,84,86], prospective cohort creating insoluble or malabsorption of L-T4,
(carbonate, acetate, tablets to oral liquid
study [77], uncontrolled clinical sparingly soluble complexes impaired efficacy of treatment
citrate) form/gel capsules
study [87], non-randomized in the intestine
monitor thyroid parameters
cross-over study [85]
more frequently
advise to delay intake by 2–4 h after
L -T4 administration
case reports [89–91], unspecific adsorption of L-T4,
Iron consider changing formulation from
retrospective cohort study creating insoluble or malabsorption of L-T4,
(ferrous citrate tablets to oral liquid
[11,93], uncontrolled clinical sparingly soluble complexes impaired efficacy of treatment
and fumarate) form/gel capsules
study [88] in the intestine
monitor thyroid parameters
more frequently
advise to delay intake by 2–4 h after
L -T4 administration
unspecific adsorption of L-T4,
consider changing formulation from
Aluminium case reports [93,94], creating insoluble or malabsorption of L-T4,
tablets to oral liquid
(hydroxide) uncontrolled clinical study [75] sparingly soluble complexes impaired efficacy of treatment
form/gel capsules
in the intestine
monitor thyroid parameters
more frequently
advise to delay intake by 3–4 h after
L -T4 administration
unspecific adsorption of L-T4,
consider changing formulation from
Chromium non-randomized cross-over creating insoluble or malabsorption of L-T4,
tablets to oral liquid
(picolinate) study [98] sparingly soluble complexes impaired efficacy of treatment
form/gel capsules
in the intestine
monitor thyroid parameters
more frequently
uncontrolled clinical study
consider advising concomitant
Vitamin C [100], non-randomized lowering of gastric pH enhanced absorption of L-T4
ingestion of vitamin C and L-T4
cross-over study [99]
Pharmaceuticals 2021, 14, 206 15 of 20

For L-T4 the knowledge gaps on drug-food interactions are clearly visible. Heuberger [106]
and Paśko et al. [107] provided a few reasons for that, such as undefined framework study,
hardly available appropriate samples, or measurement difficulties. Moreover, general lack
of understanding of the clinical significance of drug-food interactions, their cost, and overall
impact on the population, contribute to underestimating this problem.

2.14. Recommendations
Although credible data are limited, Table 2 below presents the summary of sig-
nificant interactions of L -T4 and food ingredients, as well as recommendations for
health professionals.

3. Materials and Methods

3.1. Search Strategy
A systematic search of the literature was performed by two independent researchers
AW and PP, in adherence to the preferred reporting items for systematic reviews and
meta-analyses (PRISMA) statement. The databases searched under the paper were Med-
line (via PubMed), Cochrane Library, and Embase covering reports from 1965 to 2020.
We applied the following keywords and phrases to complete the searches: drug name
(“levothyroxine”, “L-thyroxine”,” L-T4”) in combinations with “pharmacokinetics”, “food”,
“food-drug interaction”, “meal”, “fruit”, “juice”, “coffee”, “soybeans”, “milk”, “enteral
nutrition”, “iron”, “aluminum”, “calcium”, “chromium”, “fiber”, “papaya”, “vitamin C”.
Other resources such as drugs.com, AHFS, Google Scholar, Medscape, Trip Database and
UpToDate, were also researched, as well as product characteristics for the registered L-T4
formulations. Additional publications were found by checking the reference lists.

3.2. Inclusion and Exclusion Criteria

All articles reporting or investigating the effect of meals, beverages, and dietary sup-
plements, but also the dosing regimen on L-T4 pharmacokinetics and pharmacodynamics
were considered for inclusion in this review, without restriction for study design, sample
size or participants characteristics. We decided to evaluate all existing data to obtain
sufficient results to present reliable and useful recommendation for physician, pharmacist,
and patients. Exclusion criteria were: review studies, in vitro studies and articles written
in languages other than English.

3.3. Data Extraction

The extracted data included the following information: study design, number of
participants and their health state, duration of treatment, L-T4 dose and formulation, quali-
tative and quantitative composition of food, period between L-T4 and food consumption,
and reported outcomes.

4. Conclusions
The results of the reliable studies (RCT and meta-analysis) proved that L-T4 ingestion
in the morning and at bedtime are equally effective. There is strong evidence (from RCT)
to support the conclusion, that recommended administration of L-T4 with the given food
depends on its formulation. Tablets should be taken 60 min before a meal; oral liquid and
soft gel capsule forms can be ingested with food if that can improve patient adherence with
the treatment.
We found limited evidence from non-randomized cross-over studies, uncontrolled
clinical trials, and cohort studies, for the interactions between L-T4 and coffee, soy products,
fiber, calcium or iron supplements, enteral nutrition - all resulting in decreased L-T4
absorption.
We presented reports indicating altered L-T4 efficacy when ingested with milk, juices,
papaya, aluminium containing preparations, and chromium supplements, however, the
clinical relevance of these interactions should be further investigated in larger, well-
Pharmaceuticals 2021, 14, 206 16 of 20

designed studies. The possible enhancing effect of vitamin C on L-T4 absorption needs to
be proven on a larger group of patients as well.
Switching from tablets to novel formulations can solve the problem of coffee-, calcium-,
and iron-induced malabsorption of L-T4. Maintaining an interval between L-T4 and food
ingestion may also lower the risk of interactions, especially with coffee, and calcium or
iron supplements.
This review may contribute to a better understanding of L-T4 -food interactions among
physicians and pharmacists. We hope that this will also result in the increase in patients’
awareness of the proper use of L-T4. However, more in-depth reliable studies are necessary
to shed more light to the complicated but important problem of L-T4 interactions with food
and dietary supplements.

Author Contributions: Conceptualization, P.P. and A.W.; methodology P.P. and A.W; investigation,
P.P., A.W. and D.G.; resources, P.P.; writing—original draft preparation, A.W. and P.P.; writing—
review and editing, P.P and D.G.; visualization, A.W.; supervision, P.P.; project administration, P.P.;
funding acquisition, P.P. All authors have read and agreed to the published version of the manuscript.
Funding: This work was financed and supported by grant Social Responsibility of Science (SONP/SP/
461418/2020) Polish Ministry of Education and Science “Interaction between drugs and food—
knowledge, awareness, effectiveness and safety”.
Conflicts of Interest: The authors declare no conflict 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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