SIMULTANEOUS INTAKE OF LIQUID L-T4 FORMULATION AND IRON SALT: FACT OR FICTION?

Abstract

Context

Hypothyroidism and iron deficiency are among the most common pathologies in population. Therefore, there are a lot of patients assuming both iron salt supplements and levothyroxine therapy.

Objective

To evaluate the effect of iron salt intake on L-T4 absorption among different L-T4 formulations.

Materials and methods

A PubMed/MEDLINE, Web of Science, and Scopus research was performed. Original studies and reviews written in English and published online up to 21 December 2022 were selected and reviewed. The final reference list was defined based on the relevance of each paper to the scope of this review.

Results

The data show an impaired absorption of L-T4 in tablets formulation when taken concomitantly with iron salt supplements. These phenomena seem to be circumvented by new L-T4 formulations.

Conclusion

Liquid L-T4 formulations can be ingested with iron salts, with no impairment of absorption. More studies are necessary to confirm these data for soft-gel capsules L-T4.

INTRODUCTION

In community surveys, hypothyroidism affects up to 5% of the general population, with a further estimated 5% undiagnosed (1-3). Levothyroxine (L-T4) is the gold standard treatment for this condition and is the second most prescribed drug in the United States (4, 5).

Historically, the first available therapy consisted in natural thyroid preparations (thyroid extract or desiccated thyroid), containing both triiodothyronine (T3) and thyroxine (T4). Synthetic L-T4 has been available since 1950 and nowadays different formulations of it are produced, such as tablets, drops, liquid solution and soft-gel capsules (6). Levothyroxine is absorbed in the small intestine, specifically in the duodenum, jejunum, and ileum. Empty stomach is necessary for an optimal absorption, since tablets dissolution needs a very low pH (1-3, acid) (7). Many conditions can modify gastric pH thus reducing L-T4 availability, such as Helicobacter pylori infection, Celiac sprue, lactose intolerance (7), and food intake (7-9). Moreover, many drugs are known to interfere with tablet L-T4 absorption (10, 11).

Iron deficiency affects a large proportion of the world’ population, ranging from 2% in white Americans to 15% in European blood donors (12, 13). Iron salt supplementation is the milestone therapy of iron deficiency anemia (IDA) (14). Commonly available oral preparations include ferrous sulfate, ferrous gluconate and ferrous fumarate. All three forms are well absorbed but differ in elemental iron content (15). Indeed, ferrous sulfate is among the most prescribed drugs worldwide (16) owing to its favorable bioavailability and efficacy (17).

Iron salts are known to impair L-T4 absorption when taken closely in time (7, 18, 19), even if the mechanism is still unknown. New L-T4 formulations seem to circumvent many causes of its malabsorption. The aim of this review is to evaluate the efficacy of new L-T4 formulations in patients on iron salt supplementation.

METHODS

The review was conducted according to the PRISMA statement, and the checklist is reported as Supplementary file 1. A PubMed/MEDLINE, Web of Science and Scopus research was performed, for free-text words and terms related to “levothyroxine”, “iron salt”, “ferrous sulfate”, “l-thyroxine”. Original studies and reviews written in English and published online up to December 21, 2022, were selected. The final reference list was defined based on the relevance of each paper to the scope of this review.

RESULTS

In the preliminary search, 285 studies were identified and 225 remained after removal of duplicates. A total of 33 articles were eligible for full-text screening and 12 full-text publications were included in the analysis. A PRISMA flow diagram of the screening and selection process can be found in Figure 1.

Figure 1.

PRISMA Flowchart.

In detail, one was an uncontrolled clinical trial, 10 observational studies (3 prospective and 7 retrospective) and 1 a surveillance project. The studies were published between 1992 and 2022.

The articles retrieved reported the effect of iron salts on L-T4 absorption in 1,221 patients, 5,764 of whom taking tabs, as shown in Table 1, and 647 taking a new formulation (644 liquid and 3 soft-gel capsules), as shown in Table 2. In detail, iron salt supplementation was obtained with ferrous sulfate when described (Tables 1 and 2).

Table 1.

Summary of clinical studies and case reports about iron salts and levothyroxine tablets

Author, date	Study design	Patients	Interfering drug	Levothyroxine formulation	Outcome
Campbell, 1992	Uncontrolled clinical trial	14	Ferrous sulfate	Tablet	High serum TSH, no significant serum fT4 level variation; sign and symptoms of hypothyroidism. In vitro insoluble ferric-thyroxine complexes
Irving, 2015	Retrospective population analysis	429	Iron supplements	Not specified	Statistically significant increase of serum TSH levels
McMillan, 2015	Control surveillance project	110	Iron supplements	Not specified	Iron could interfere with L-T4 absorption
Atruktsang, 2019	Retrospective cohort study	15	Iron supplements	Not specified	Iron could be associated with L-T4 prolonged dose adjustment in thyroidectomy patients
Dias, 2019	Retrospective analysis	4	Ferrous sulfate	Levothyroxine sodium	Reduce L-T4 serum levels
Tukukino, 2022	Retrospective analysis	2	Ferrous sulfate	Not specified	Ferrous sulfate decreased effect of L-T4

Table 2.

Summary of clinical studies and case reports about iron salts and new formulation of levothyroxine

Author, date	Study design	Patients	Interfering drug	Levothyroxine formulation	Outcome
Brancato, 2014	Retrospective observational study	4	Ferrous sulfate	Tablet vs. liquid	Statistically significant reduction of serum TSH levels with liquid vs. tablet
Benvenga, 2017	Prospective observational cohort study	8	Ferrous sulfate	Tablet vs. liquid	Reduction of TSH levels after 6 weeks of switch
Vita, 2017	Prospective non-randomized cohort study	4	Ferrous sulfate	Tablet vs. liquid	Statistically significant reduction of TSH levels after 6 weeks of switch
Ferrara, 2017	Observational study	67	Ferrous sulfate	Tablet vs. liquid	Statistically significant reduction of TSH levels after switch
Guglielmi, 2017	Retrospective observational study	558	Iron salt	Tablet vs. liquid	Switching at liquid formulation is not associated with increase prescribed daily dosage
Benvenga, 2019	Prospective observational cohort study	3	Iron supplements	Tablet vs. liquid vs. soft gel	Greater bioavailable of L-T4 with liquid and soft gel formulation. Decrease of TSH level

Campbell et al. conduced a clinical trial on 14 patients taking a stable dose of L-T4 to which ferric sulfate (300 mg daily) was simultaneously added for 12 weeks. The Authors showed a significant increase of serum TSH levels [from 1.6±0.4 to 5.4±2.8 mU/L (p < 0.01)] with no change in serum free thyroxine (fT4) levels. In addition, they showed the appearance of a poorly soluble complex when iron was mixed to thyroxine in vitro (18).

In agreement with the above studies, Irving et al. showed, in a large series of patients (429 subjects) under stable L-T4 dosage for at least two years, a significant serum TSH increase (0.22 mU/L, p < 0.001) after concomitant iron supplementation (20). The need for L-T4 dosage adjustment was reported in a hypothyroid patient when iron supplements were added (21), data confirmed in few patients submitted to thyroidectomy (22). Drug interactions, mainly in older people, between levothyroxine and iron supplementation was recently reported both in primary care subjects and in those discharged from hospital (23, 24).

Differently, Brancato et al. in 4 patients on sulfate ferrous supplementation retrospectively showed an increase in L-T4 absorption rate when liquid L-T4 was taken in comparison to tablets (25). These data were confirmed by Benvenga et al. who prospectively showed no interference in 8 patients taking ferrous sulfate concomitantly with liquid L-T4. In particular, they showed a significant serum TSH reduction after switching from tablet to liquid formulation at the same dosage (8.74 ± 7.2 vs. 1.68 ± 0.9, respectively, p< 0.001) (26). The same group confirmed this data in another prospective study on 11 patients (27). Guglielmi et al. analyzed the data of the Italian General Practice Health Search Database showing that the use of L-T4 liquid formulations in patients with hypothyroidism, most of whom on iron supplementation, overcame drug-induced L-T4 malabsorption (28). Similar results were obtained by Ferrara et al. in a population-based study (29).

Lastly, Benvenga demonstrated that the absorption of soft gel L-T4 capsules is superimposable to liquid formulation in 3 patients simultaneously taking iron supplements (30).

DISCUSSION

Levothyroxine is the milestone of hypothyroidism treatment (4). The maintenance of serum TSH level within the referral range is mandatory to avoid possible dangerous effects of hypo- or-hyperthyroidism, both in young and in older people (31, 32). Many conditions are known to interfere with tablets L-T4 absorption, such as their co-ingestion with coffee and several drugs (7, 10, 33).

Since in the early 2010s pharmaceutical factories developed new L-T4 formulations (liquid, soft gel), they appeared to demonstrate different properties. First, Brancato et al. showed greater L-T4 absorption in 53 patients after switching from tablets to liquid formulation (25), thus confirming previous studies of bioequivalence (34). Later, several studies were carried out to demonstrate the better pharmacokinetics of new formulations in different conditions known to impair L-T4 absorption (8). Nowadays, it is therefore reasonable to take liquid formulations, which are to be preferred in patients at risk of L-T4 malabsorption (11).

One-third of population is affected by iron deficiency and iron salts are commonly prescribed worldwide (35). Considering the high prevalence of hypothyroidism and iron deficiency, it is not infrequent that a patient suffers of both and is on concomitant therapy with L-T4 and iron salts. Most important, hypothyroid pregnant women on iron supplementation must be taken into account (36).

It is important to underline that tablets L-T4 absorption is reduced when it is taken simultaneously with iron salts (18, 20, 21, 24). The mechanism is still unclear; however, it has been hypothesized that different functional groups (phenolic, carboxylate) of L-T4 could form insoluble or sparingly soluble complexes with ferrous salts (18, 37) reducing the intestinal barrier transit. For this reason, it has been suggested to separate the times of administration of levothyroxine and iron-containing preparations by at least 2 to 4 hours (4, 18). However, drugs temporal separation reduces patients’ compliance and adherence to therapies (48). Differently, liquid L-T4 seems to circumvent this problem (8, 25, 28, 39). Moreover, our group has recently shown that this new formulation can be taken simultaneously with drugs (mainly proton pump inhibitors) that usually interfer with L-T4 absorption (16).

Keeping in mind the issue of impaired L-T4 absorption due to simultaneous intake of iron salts, a subgroup analysis of the study by Brancato et al. aimed to evaluate whether serum TSH levels were influenced by switching from tablets to liquid L-T4. They showed that iron salts did not reduce liquid L-T4 absorption at least in 4 patients (25). Two prospective studies confirmed and extended this observation, showing that liquid L-T4 seems to be refractory to iron salts interfering (26, 27).

Moreover, Guglielmi et al., in a large set of hypothyroid patients, most of whom on iron supplementation, formulations overcame drug-induced L-T4 malabsorption (28). In addition, Ferrara et al., in a population-based study carried out from 2009 to 2015, showed greater stability of TSH serum levels in levothyroxine users after switching from tables to liquid formulation. This was particularly evidenced in patients showing reduced intestinal absorption of tablets as well as in patients taking iron salts (28).

To the best of our knowledge, there is only one study that analyzed the co-ingestion of soft-gel capsules and iron salts and found promising results in 3 patients (25).

To date, no explanations are available as to why liquid L-T4 formulations escape drugs interference. Vita et al. hypothesized three possible mechanisms. Firstly, liquid formulations do not need dissolution phase, thus they are not affected by changes in the gastric pH which is crucial for tablets absorption. Secondly, liquid formulations seem to be refractory and/or resistant to drugs sequestration. Finally, the ethanol present in the liquid formula could increase blood gastrointestinal flow, thus ameliorating L-T4 absorption (27).

In conclusion, the available data show that liquid formulation can be ingested with iron salts and therefore simplify the management of L-T4 treated hypothyroid patients. More studies are necessary to confirm this data for soft-gel capsules and also for different ferrous formulations than ferrous sulfate.

Conflict of interest

The authors declare that they have no conflict of interest.