Endocrine (2018) 59:585–592
DOI 10.1007/s12020-017-1412-4
ORIGINAL ARTICLE
Drug interactions in users of tablet vs. oral liquid levothyroxine
formulations: a real-world evidence study in primary care
Valeria Guglielmi1 Alfonso Bellia1 Elisa Bianchini2 Gerardo Medea3
● ●
Iacopo Cricelli2 Paolo Sbraccia1 Davide Lauro1 Claudio Cricelli3 Francesco Lapi2
● ● ● ●
Received: 6 June 2017 / Accepted: 28 August 2017 / Published online: 14 September 2017
© Springer Science+Business Media, LLC 2017
Abstract
Purpose Several medications may interact with levothyr-
oxine (LT4) intestinal absorption or metabolism, thus
reducing its bioavailability. We investigated the variability
of thyroid stimulating hormone (TSH) levels and prescribed
daily dosages (PDDs) of LT4 before and during potential
drug–drug interactions (DDIs) in users of tablets vs. oral
liquid LT4 formulations.
Methods By using the Italian general practice Health
Search Database (HSD), we retrospectively selected adult
patients with at least one LT4 prescription from 2012 to
2015 and at least 1 year of clinical history recorded. The
incident prescription of interacting medications (e.g., proton
pump inhibitors, calcium or iron salts) was the index date.
Analysis was carried out using a self-controlled study
design.
Results Overall, 3965 users of LT4 formed the study cohort
(84.1% women, mean age 56 ± 16.5 years). TSH variability
on the entry date was greater among liquid LT4 users than
in those prescribed with tablets as shown by the difference
between 75th and 25th centile, which were 3.01 and 3.8,
respectively. The incidence rate ratio (IRR) for TSH
variability did not differ between groups, before and during
Valeria Guglielmi and Alfonso Bellia equally contributed.
* Francesco Lapi
lapi.francesco@simg.it
1
Department of Systems Medicine, University of Rome “Tor
Vergata”, Rome, Italy
2
Health Search, Italian College of General Practitioners and
Primary Care, Florence, Italy
3
Italian College of General Practitioners and Primary Care,
Florence, Italy
● ●
exposure to DDIs. In contrast, PDDs less likely increased
during the exposure to DDI with oral liquid LT4 compared
with tablets (IRR = 0.84; 95% CI: 0.77–0.92), especially in
patients with post-surgical hypothyroidism (IRR = 0.75;
95% CI: 0.64–0.85).
Conclusions In clinical practice, the use of oral liquid LT4
is not associated with increased PDDs, compared with
tablets formulation, during exposure to DDIs. These results
support the need for individualizing LT4 formulation to
prescribe, especially in patients with various comorbidities
and complex therapeutic regimens.
Keywords Tablet levothyroxine Oral liquid levothyroxine
● ●
Drug–drug interactions Gastrointestinal absorption
● ●
Primary care Prescribed daily dosages
●
Introduction
Clinical and sub-clinical hypothyroidism are estimated to
occur in about 0.4% and 4–8% of Western population,
respectively [1]. The most common cause of primary
hypothyroidism is low iodine dietary intake in geographical
areas with severe iodine deficiency, whereas autoimmune
thyroiditis, previous treatment with radioiodine or thyr-
oidectomy are predominant in countries with mild iodine
deficiency or sufficient iodine intake [1, 2].
Nowadays, oral levothyroxine (LT4) represents the cor-
nerstone in the treatment of hypothyroidism [1].
LT4 is traditionally available in tablet formulation, which
need to be dissolved in the acid gastric pH prior to its
absorption at the levels of duodenum and jejunum [3, 4].
Approximately 70% of the LT4 contained in the tablet is
586
completely absorbed, but several conditions, such as gas-
trointestinal diseases (e.g. gastroenteritis, Helicobacter
pylori infections, parasite colonization, lactose intolerance,
intestinal ischemia, atrophic gastritis, celiac disease and
inflammatory bowel diseases) [5–7], surgical interventions
at gastrointestinal level (small intestine resection or bariatric
surgery) [8–11], as well as the co-administration of certain
interacting foods, beverages [12–14] or drugs can impair its
absorption. In particular, various frequently used medica-
tions, such as proton pump inhibitors (PPIs), ferrous sul-
phate, sucralfate, raloxifene, bile acid sequestrants, calcium
carbonate, phosphate binders, and aluminum-containing
antiacids have been demonstrated to interfere with LT4
absorption, either by increasing gastric pH (the case of
PPIs) or binding LT4 into insoluble complexes (the case of
calcium or iron salts) [10]. Other types of drugs reduce the
bioavailability of LT4, accelerating T4 metabolism by the
induction of the hepatic enzyme uridine diphosphate glu-
curonosyltransferase (the case of many antiepileptic drugs,
such as phenobarbital, phenytoin, carbamazepine, valproate
and oxcarbazepine) and/or the biliary excretion of iodo-
thyronine conjugates (the case of rifampicin)[9], altering
the protein binding [15] or interfering with the
hypothalamic–pituitary–thyroid axis function (the case of
carbamazepine) [16].
To overcome the issue of LT4 tablet absorption, new oral
liquid formulations, including pre-dosed ampoules, oral
drops (LT4 dissolved in glycerin and ethanol) and soft gel
capsules (LT4 dissolved in glycerine within a gelatin shell),
have been marketed in the recent years. These novel for-
mulations display similar pharmacokinetic properties com-
pared to LT4 tablets [17], and are resistant to gastric pH
variations and are characterized by higher bioavailability
[18–20]. These findings have been confirmed by recent
clinical studies reporting significant reductions of TSH
levels [21–25] and measurement frequency (as proxy of
clinical efficacy) in patients switching from tablets to oral
liquid LT4 formulations [26] in the absence of malabsorp-
tion or drug interference. In addition, oral liquid solutions of
LT4, not requiring dissolution and speeding up the
absorption as compared to tablets [17, 18, 27], have been
demonstrated to circumvent LT4 malabsorption in cases of
gastrointestinal diseases [28–30] and surgery [31, 32].
When it comes to the effects of drug–drug interactions
(DDIs) during LT4 therapy, few observational studies in
clinical practice have been carried out so far. Furthermore,
those studies were mostly limited to case series [33] or
small groups of patients [22, 34] in specific settings and/or
medical conditions [35] or healthy volunteers [36, 37], thus
not adequately representing the general population.
Therefore, in light of the large use of concurrent thera-
pies interfering with LT4 bioavailability and the limited
real-world data on LT4 liquid formulations in Italy, the
Endocrine (2018) 59:585–592
present study aimed to analyze the Italian general practice
patients exposed to tablets vs. liquid formulation LT4, in
terms of variation of TSH level and prescribed daily dosa-
ges (PDDs) of LT4, as tablet and liquid formulation, before
and during potential DDIs, using the Italian Health Search
IMS Health Longitudinal Patient Database (HSD) [38, 39].
Materials and methods
Data source
The study was conducted using the Italian general practice
Health Search IMS Health Longitudinal Patient Database
(HSD). This data source is formed by a network of
approximately 1000 general practitioners (GPs) from all
over Italy who voluntarily electronically register clinical
patients’ data from their routine clinical practice and attend
training programs related to data entry. To be considered
eligible for epidemiological studies, GPs need to be con-
sistent with “up-to-standard” quality criteria including
accuracy of coding, prevalence of selected diseases, rates of
mortality, and years of recording. For the present study we
identified 800 GPs, homogeneously distributed across all
Italian areas, whose data entries fulfilled quality criteria and
cover an overall population of almost 1.3 million of
patients.
The HSD contains anonymized clinical data (diagnoses,
patient referrals, hospital admissions, and clinical investi-
gations’ results) and prescription data (drug name, pre-
scription date, number of days’ supply) for all the
medications which are reimbursed by the National Health
System (NHS). Data within the HSD is coded using inter-
nationally recognized codes such as the Anatomical Ther-
apeutic Chemical (ATC) classification system for drugs and
the 9th version of the International Classification of Dis-
ease, Clinical Modification (ICD-9-CM) for medical diag-
noses. The reliability of HSD for conducting clinical
research has been demonstrated elsewhere [40–43].
Study population
We identified all patients aged 18 years or older being
prescribed with any formulation of LT4 (ATC: H03AA01)
between 1st January 2012 and 30th June 2015, time frame
selected on the basis of oral liquid formulations availability
in the market. The date of the LT4 prescription being
registered during the enrollment period was considered the
study entry date. Patients were considered eligible whether
they had at least 1 year of clinical history recorded in HSD
before the entry date, and were excluded if they were pre-
scribed one of the drugs which may interact with LT4 (see
the section ‘Exposure assessment’) before the entry date,
Endocrine (2018) 59:585–592
had a diagnosis of cancer, had no TSH measurements along
with a follow-up shorter than 45 days (so including 15 days
of latency period, see ‘Exposure assessment’) after being
prescribed with the interacting drug. The date of the first
prescription for a potentially interacting drug was con-
sidered the study index date. Eligible patients were therefore
followed up until the detection of exclusion criteria reported
above, being transferred out, death, or end of data avail-
ability (30th June 2016), whichever came first.
Exposure assessment
The exposure was operationally assessed as the concurrent
prescription of LT4 with potentially interacting drugs such
as proton-pump inhibitors (PPIs) (ATC: A02BC*), calcium
carbonate (A12AA04), aluminum hydroxide and magne-
sium hydroxide (A02AD01), sucralfate (A02BX02), orlistat
(A08AB01), ferrous sulphate (B03AA07), cholestyramine
(C10AC01), sevelamer (V03AE02), which are able to
impair absorption of levothyroxine, and carbamazepine
(N03AF01), phenytoin (N03AB02), phenobarbital
(N03AA02), estrogens (G03C*) and raloxifene
(G03XC01), which might alter both binding to plasmatic
proteins and metabolism of LT4. In line with prior inves-
tigations, we excluded estrogen–progestin combinations
because the pharmacological effects of one hormone on
TSH may be counter-balanced by the other [44], potentially
leading to unexpected TSH fluctuations. We also excluded
medications with proven minor clinical relevance [45, 46].
Outcome assessment
We investigated how the variation of TSH levels (mIU/L)
and Prescribed Daily Doses (PDDs) of tablet or liquid oral
formulations of LT4 was modified by concomitant pre-
scription with potentially interacting drugs. Both outcomes
were measured at least 15 days after the co-prescription of
the potentially interacting drugs (i.e. index date plus at least
15 days) in order to have a biologically plausible timeframe
for a pharmacological interaction to take place [45].
Data analysis
A pre–post analysis was carried out using a self-controlled
study design. We employed generalized linear latent models
for data pairs, for which we adopted gamma and Poisson
distribution for TSH levels and PDDs, respectively. Every
model comprised a two-level variable concerning prescrip-
tions of tablet or oral liquid levothyroxine formulations, and
another two-level variable defining the pre–post potential
drug–drug interaction phase. By doing so, we were able to
compare tablet vs. oral liquid formulation within pre- or
during potential drug interaction (post-phase) by including
587
in the model an interaction term, composed of pre–post
interaction phase and formulation variables. The multi-
variable model therefore showed the effect on TSH levels
exerted by co-prescription of tablet vs. oral liquid LT4
formulation at baseline (pre-phase), while what occurred in
the post-phase was assessed by combining the aforemen-
tioned interaction term with the variable coding the pre–post
interaction phase. Prescription of tablet formulations was
the reference category for every analysis.
Since this was a self-controlled study, patient data before
and during the potential drug–drug interaction were com-
pared with regards to the outcome over the same length of
the study periods. For instance, for a patient with a 6-month
follow-up after the index date (i.e., censored after
6 months), the outcome was measured during the 6 months
before the index date.
Multivariate model was estimated adjusting by tertile
categories of serum TSH levels and therapeutic indication
for LT4 use, as well as for potential confounders which had
been operationally identified before or on the entry date.
They included alcohol abuse or alcohol-related disease, last
recorded smoking status before the entry date (smoker, ex-
smoker, non-smoker), last recorded body mass index (BMI)
before the entry date for patients >20 Kg/m2, ICD-9-CM
reported diagnosis of cardiovascular diseases, rheumatoid
arthritis, liver failure/cirrhosis, chronic kidney disease,
depression, gastrointestinal diseases related to malabsorp-
tion disorders (Crohn’s disease, ulcerative colitis, celiac
disease).
As secondary analysis, we reran the model after stratifi-
cation by therapeutic indication of LT4. This is because the
needed dosages of LT4 replacement therapy can be affected
in some ways by the underlying cause of hypothyroidism
(e.g. patients who underwent thyroid surgery are not influ-
enced by the residual thyroid function as otherwise occurs
in other forms of primary hypothyroidism).
Results
Table 1 shows baseline demographics and clinical char-
acteristics of 3965 patients who received at least one LT4
dispensing during the years 2012–2015, stratified by LT4
formulation (tablet, liquid or mixed, the latter defined as
randomly switching to liquid or solid formulation of LT4).
Female gender was predominant (84.1%) with mean age of
56 ± 16.5 years. Most of LT4 users received tablets (N =
3643; 91.8%). Among the various causes of acquired pri-
mary hypothyroidism post-surgical hypothyroidism repre-
sented the indication for LT4 use in 23.4% of tablet users
and 26.9% of liquid LT4 users. Overall, proportions of
patients affected by diseases that could impair LT4 circu-
lating levels were small and similarly distributed among
588 Endocrine (2018) 59:585–592

Table 1 Clinical features of the study population stratified by LT4 Table 2 TSH variation before and during DDI exposure
formulation (tablet, liquid or mixed) at the index date
IRR (IC 95%) IRR (IC 95%)a
Tablet Liquid Mixed Crude Adjusted
N (%) N (%) N (%)
Formulation (before DDI exposure)
Sex Tablet Ref. Ref.
Females 3059 48(88.89) 55(83.33) Liquid 1.28 (0.70–2.33) 1.13 (0.65–1.95)
(83.97)
Mixed 1.73 (1.27–2.35) 1.35 (0.88–2.05)
Males 584(16.03) 6(11.11) 11(16.67)
Formulation (during DDI exposure)
Age (years) (mean [SD]) 56.21 49.19 49.87
(16.50) (16.11) (14.15) Tablet Ref. Ref.
Indication for prescription Liquid 1.36 (0.78–2.38) 1.42 (0.81–2.48)

Primary acquired 2139 38(67.31) 36(83.72) Mixed 1.80 (1.16–2.79) 1.87 (1.21–2.90)
hypothyroidism (76.20) a
for all the variables listed in Table 1
Post-surgical 655(23.44) 14(26.92) 7(16.28)
hypothyroidism
TSH (mIU/L) (median (IQR) 2.15(3.01) 1.82(3.8) 2.92(4.06)
difference) Table 3 PDDs variation before and during DDI exposure
BMI IRR (IC 95%) IRR (IC 95%)a
≤20 kg/m 2
127(3.49) 2(3.70) 4(6.06) Crude Adjusted
>20 kg/m 2
1907 26(48.15) 33(50)
Formulation (before DDI exposure)
(52.35)
Tablet Ref. Ref.
Missing 1609 26(48.15) 29(43.94)
(44.17) Liquid 0.81 (0.77–0.85) 0.84 (0.76–0.90)
Co-morbidities Mixed 0.92 (0.86–0.98) 0.93 (0.86–1.02)
Osteoartrosis 747(20.51) 8(14.81) 10(15.15) Formulation (during DDI exposure)
Depression 554(15.21) 6(11.11) 10(15.15) Tablet Ref. Ref.
Cardiovascular diseases 257(7.05) 2(3.70) 3(4.55) Liquid 0.83 (0.78–0.88) 0.84 (0.77–0.92)
Hepatic failure/cirrhosis 132(3.62) 4(7.41) 1(1.67) Mixed 0.93 (0.86–1.0) 0.93 (0.84–1.03)
Chronic kidney disease 84(2.31) 0 0 a
for all the variables listed in Table 1
Malabsorption diseases 44(1.21) 2(3.70) 2(3.03)
Rheumatoid arthritis 38(1.04) 0 0
Helicobacter pylori 34(0.93) 0 0 The mostly used interacting medications encompassed
infection
proton pomp inhibitors (n = 3233 [88%]) and calcium or
Atrophic gastritis 19(0.52) 0 0 iron salts (n = 558 [15.2%]).
Alcohol abuse and alcohol- 21(0.58) 0 0 Table 2 shows the results of uni- and multivariate models
related diseases
estimated to test the hypothesis of an association between
Food intolerance 17(0.47) 0 0
use of different LT4 formulations and TSH variations. The
BMI body mass index, IQR interquartile range, TSH thyroid incidence rate ratio (IRR) comparing users of oral liquid vs.
stimulating hormone tablet formulations in terms of TSH changes, showed
nonsignificant differences, both before (adjusted IRR =
groups, including alcohol abuse (0.5%), severe chronic 1.13 [95% [CI]: 065–1.95]) and during the period of
kidney (2.1%) and hepatic (3.5%) disease, depressive dis- exposure to potential DDI (adjusted IRR = 1.42 [95% [CI]:
order (15%), atrophic gastritis (0.5%), gastritis associated 0.81–2.48]) (Table 2). Similarly, nonsignificant differences
with Helicobacter pylori infection (0.8%), lactose intoler- were seen between mixed LT4 therapy vs. tablet users,
ance, celiac disease, and intestinal malabsorption (1.2%). during both period of observation (Table 2).
TSH variability on the entry date was greater in users of Results on PDDs variation between groups are given in
liquid LT4 than those prescribed with tablets (Table 1), as Table 3. Namely, the odds of PDDs variation significantly
shown by the Interquartile ranges (IQRs) difference decreased by nearly 16% in oral liquid LT4 users compared
(defined as75th minus 25th centile), which were 3.01 and with tablet users both before (IRR = 0.84; 95% CI:
3.8 in patients treated with tablet and oral liquid formula- 0.76–0.90) and during the DDI exposure period (IRR =
tions of LT4, respectively. Similarly, TSH variability at 0.84; 95% CI: 0.77–0.92). Of interest, this observed dif-
baseline was higher in patients having switched formulation ference in the rates of PDDs variability during DDIs
when compared with tablet users. exposure between oral liquid and tablets was even more
Endocrine (2018) 59:585–592
pronounced in the subgroup of patients treated for post-
surgical hypothyroidism (IRR = 0.75; 95% CI: 0.64–0.85).
Discussion
To our knowledge, this is the first population-based study
investigating potential differences between tablets and oral
liquid LT4 formulations in terms of maintenance of desired
circulating levels of hormones whenever co-prescribed with
potentially interacting medications. To do so, we took
advantage of a sizeable sample of LT4 users (about 4000
individuals) representative of the Italian general population.
Overall, we found that the use of oral liquid LT4, compared
with LT4 tablets, was associated with less need for PDD
increase during DDI exposure, in order to maintain TSH
levels stable.
During the observation period (2012–2015), LT4 liquid
users initially showed an overall higher TSH variability
compared to patients treated with tablets. This observation
should be however interpreted with caution. Indeed, we
cannot rule out, as possible explanation, that patients suf-
fering from multiple comorbidities and treated with com-
plex therapeutic regimens were more prone to be channeled
towards LT4 liquid formulation by their physicians [47]. In
this sense, the use of liquid LT4 formulation could serve as
proxy for the burden of disease and multiple treatments,
which inherently carry an increased risk of TSH instability,
so determining a risk of channeling bias for this unexpected
result in our analysis.
Reduced LT4 absorption is associated with increased
TSH values, generally prompting clinicians to increase the
daily dose of LT4, or otherwise to shift the patient to more
bio-available formulations. In accordance, the co-
prescription of LT4 and potentially interacting drugs
resulted in an increased dosage prescription of LT4 tablets,
which likely explains the absence of a significant increase
of TSH levels. Similarly, switching from tablet to liquid
LT4 formulations entailed a greater increase in LT4 dosage
during DDI, as already reported for drugs with a narrow
therapeutic index [48]. Indeed, even small deviations in
bioavailability have the potential to result in loss of TSH
steadiness in some patients.
The few previous observational studies investigating the
effects of DDI during LT4 therapy in real-life setting were
mainly limited to local [33] and small groups of patients
[22, 34–37], or did not specifically investigate the DDIs
effects on variations of TSH levels [49] and LT4 prescribed
dosages [50].
In this context, our study adds real-world information
collected from a primary care database, and confirms that
LT4 liquid formulation can be a useful choice for patients to
overcome drug-induced LT4 malabsorption and consequent
589
need for increasing daily dosage, especially whenever
diverse comorbidities are present and other potentially
interfering medications are taken by patients. Contrary to a
previous nationwide report in which the authors analyzed
HSD records on LT4 number of prescriptions during
potential DDIs regardless of the type of LT4 formulation
[45], we explored the differential effects of DDIs on LT4
liquid and tablet users choosing the PDD variation as pre-
ferred outcome best reflecting the actual therapeutic regi-
men. Furthermore, we improved on previous work, taking
into account a number of confounders that may variously
interfere with treatment effect on TSH variability, such as
age, gender and diverse comorbidities, along with per-
forming a statistical analysis which accounts for dependent
pairwise data [39]. Finally, our design minimizes the impact
of selection and recalls bias given that clinical data included
in our database are prospectively recorded [51].
This study has limitations as well. First, the analysis is
based on prescriptions data, so that we cannot ascertain
whether the drugs were actually taken by patients. How-
ever, differences in the adherence to LT4 therapy between
formulations have not been so far reported, reason why
the risk of misclassification would have been non differ-
ential between the compared groups. As such, the statis-
tically significant differences we captured between groups
are reassuring [52]. Second, we included only patients
treated with LT4 for acquired primary hypothyroidism
due to various causes including thyroidectomy. Never-
theless, the lower probability to increase the PDDs of oral
liquid LT4 during DDIs exposure resulted independent of
the underlying diagnosis. In addition, subgroup analysis
revealed these inter-groups differences were more pro-
nounced in individuals with post-surgical hypothyroid-
ism, namely a clinical condition in which the thyroid
hormone replacement therapy is not influenced by the
residual thyroid function as possibly occurs in other forms
of primary hypothyroidism. Finally, since soft gel cap-
sules are not covered by National Health Service and our
analysis did not take into account LT4 prescriptions pri-
vately purchased, exposure misclassification for newer
formulations may be larger than that for tablets. However,
we believe this risk of misclassification is quite low on our
study (17 prescriptions out of 1012 (1.7%) for liquid
formulations), since the number of these prescriptions was
negligible.
In conclusion, these real-world data from primary care
setting can support the use of LT4 liquid formulations in
patients with hypothyroidism in order to overcome drug-
induced LT4 malabsorption. Using of these formulations
may foster TSH stability, especially in individuals with
comorbidities undergoing complex therapeutics regimens.
In addition, with the reduced rates of TSH variability and
need for daily dosage increase, patients are actually more
590
protected against the risk of exposure to excessive dose of
replacement therapy, whenever the interacting drugs are
discontinued. This is of particular relevance in patients with
or at risk of coronary artery disease, arrhythmias, and bone
fractures [53, 54]. Therefore, since optimization of LT4
replacement therapy plays a key role in the successful
management of hypothyroidism, in the scenario of diverse
LT4 formulations availability, clinicians should carefully
consider these findings to tailor patients therapy whenever
co-prescription of LT4 and potentially interacting drugs is
needed.
Funding This study was supported by IBSA. The funding institution
had no role in the design and conduct of the study, the collection,
management, analysis, and interpretation of the data, the preparation,
review, or approval of the manuscript, or the decision to submit the
manuscript for publication.
Compliance with ethical standards
Conflict of interest Dr. I. Cricelli and Dr. F. Lapi provided con-
sultancies in protocol preparation for epidemiological studies and data
analyses for Angelini, Alfa Wassermann, Bayer, and IBSA. Dr. C.
Cricelli, and Dr. G. Medea provided clinical consultancies for
Angelini, Alfa Wassermann, Bayer, and IBSA. Dr. V. Guglielmi, Dr.
A. Bellia, Dr. E. Bianchini, Prof. P. Sbraccia, and Prof. D. Lauro, have
no conflict of interest to disclose.
Ethical approval This is an observational, retrospective, non-
interventional study. According to a by-law on the classification and
implementation of observational drug-related research, as issued by the
Italian National Drug Agency (an entity belonging to the Italian
Ministry of Health), the present study does not require approval by an
Ethics Committee in Italy (Italian Drug Agency note of 3rd August
2007).
References
1. J.R. Garber, R.H. Cobin, H. Gharib, J.V. Hennessey, I. Klein, J.I.
Mechanick, R. Pessah-Pollack, P.A. Singer, K.A. Woeber, Clin-
ical practice guidelines for hypothyroidism in adults: cosponsored
by the American Association of Clinical Endocrinologists and the
American Thyroid Association. Thyroid 22(12), 1200–1235
(2012). https://doi.org/10.1089/thy.2012.0205
2. A.J. Chakera, S.H. Pearce, B. Vaidya, Treatment for primary
hypothyroidism: current approaches and future possibilities. Drug.
Des. Devel. Ther. 6, 1–11 (2012). https://doi.org/10.2147/DDDT.
S12894
3. W.E. Visser, E.C. Friesema, T.J. Visser, Minireview: thyroid
hormone transporters: the knowns and the unknowns. Mol.
Endocrinol. 25(1), 1–14 (2011). https://doi.org/10.1210/me.2010-
0095
4. M.T. Hays, Localization of human thyroxine absorption. Thyroid
1(3), 241–248 (1991). https://doi.org/10.1089/thy.1991.1.241
5. M. Centanni, L. Gargano, G. Canettieri, N. Viceconti, A. Franchi,
G. Delle Fave, B. Annibale, Thyroxine in goiter, Helicobacter
pylori infection, and chronic gastritis. N. Engl. J. Med. 354(17),
1787–1795 (2006)
Endocrine (2018) 59:585–592
6. C. Virili, G. Bassotti, M.G. Santaguida, R. Iuorio, S.C. Del Duca,
V. Mercuri, A. Picarelli, P. Gargiulo, L. Gargano, M. Centanni,
Atypical celiac disease as cause of increased need for thyroxine: a
systematic study. J. Clin. Endocrinol. Metab. 97(3), E419–E422
(2012). https://doi.org/10.1210/jc.2011-1851
7. M. Ruchala, E. Szczepanek-Parulska, A. Zybek, The influence of
lactose intolerance and other gastro-intestinal tract disorders on L-
thyroxine absorption. Endokrynol. Pol. 63(4), 318–323 (2012)
8. R. Padwal, D. Brocks, A.M. Sharma, A systematic review of drug
absorption following bariatric surgery and its theoretical impli-
cations. Obes. Rev. 11(1), 41–50 (2010). https://doi.org/10.1111/j.
1467-789X.2009.00614.x
9. G. Ianiro, F. Mangiola, T.A. Di Rienzo, S. Bibbo, F. Franceschi,
A.V. Greco, A. Gasbarrini, Levothyroxine absorption in health
and disease, and new therapeutic perspectives. Eur. Rev. Med.
Pharmacol. Sci. 18(4), 451–456(2014)
10. L. Liwanpo, J.M. Hershman, Conditions and drugs interfering
with thyroxine absorption. Best Pract. Res. Clin. Endocrinol.
Metab. 23(6), 781–792 (2009). https://doi.org/10.1016/j.beem.
2009.06.006
11. M. Lombardo, A. Bellia, F. Mattiuzzo, A. Franchi, C. Ferri, E.
Padua, V. Guglielmi, M. D’Adamo, G. Annino, P. Gentileschi, F.
Iellamo, D. Lauro, M. Federici, P. Sbraccia, Frequent follow-up
visits reduce weight regain in long-term management after bariatric
surgery. Bariatr. Surg. Pract. Patient Care 10(3), 119–125(2015).
12. S. Benvenga, L. Bartolone, S. Squadrito, F. Lo Giudice, F. Tri-
marchi, Delayed intestinal absorption of levothyroxine. Thyroid 5
(4), 249–253 (1995). https://doi.org/10.1089/thy.1995.5.249
13. T.G. Bach-Huynh, B. Nayak, J. Loh, S.Soldin, J. Jonklaas, Tim-
ing of levothyroxine administration affects serum thyrotropin
concentration. J. Clin. Endocrinol. Metab. 94(10), 3905–3912
(2009). https://doi.org/10.1210/jc.2009-0860
14. N. Bolk, T.J. Visser, J. Nijman, I.J. Jongste, J.G. Tijssen, A.
Berghout, Effects of evening vs morning levothyroxine intake: a
randomized double-blind crossover trial. Arch. Intern. Med. 170
(22), 1996–2003 (2010). https://doi.org/10.1001/archinternmed.
2010.436
15. R.D. Utiger, Estrogen, thyroxine binding in serum, and thyroxine
therapy. N. Engl. J. Med. 344(23), 1784–1785 (2001). https://doi.
org/10.1056/NEJM200106073442310
16. S.A. Hamed, The effect of antiepileptic drugs on thyroid hormonal
function: causes and implications. Expert. Rev. Clin. Pharmacol. 8(6),
741–750 (2015). https://doi.org/10.1586/17512433.2015.1091302
17. C.S. Yue, C. Scarsi, M.P. Ducharme, Pharmacokinetics and
potential advantages of a new oral solution of levothyroxine vs.
other available dosage forms. Arzneimittelforschung. 62(12),
631–636 (2012). https://doi.org/10.1055/s-0032-1329951
18. R. Vita, P. Fallahi, A. Antonelli, S. Benvenga, The administration
of L-thyroxine as soft gel capsule or liquid solution. Expert. Opin.
Drug. Deliv. 11(7), 1103–1111 (2014). https://doi.org/10.1517/
17425247.2014.918101
19. D. Pabla, F. Akhlaghi, H. Zia, A comparative pH-dissolution
profile study of selected commercial levothyroxine products using
inductively coupled plasma mass spectrometry. Eur. J. Pharm.
Biopharm. 72(1), 105–110 (2009). https://doi.org/10.1016/j.ejpb.
2008.10.008S0939-6411(08)00387-1
20. A. Cassio, S. Monti, A. Rizzello, I. Bettocchi, F. Baronio, G.
D’Addabbo, M.O. Bal, A. Balsamo, Comparison between liquid
and tablet formulations of levothyroxine in the initial treatment of
congenital hypothyroidism. J. Pediatr. 162(6), 1264–1269 (2013).
https://doi.org/10.1016/j.jpeds.2012.11.070
21. R. Vita, F. Di Bari, S. Benvenga, Oral liquid levothyroxine solves
the problem of tablet levothyroxine malabsorption due to con-
comitant intake of multiple drugs. Expert. Opin. Drug. Deliv. 14
(4), 467–472 (2017). https://doi.org/10.1080/17425247.2017.
1290604
Endocrine (2018) 59:585–592
22. R. Vita, G. Saraceno, F. Trimarchi, S. Benvenga, Switching
levothyroxine from the tablet to the oral solution formulation
corrects the impaired absorption of levothyroxine induced by
proton-pump inhibitors. J. Clin. Endocrinol. Metab. 99(12),
4481–4486 (2014). https://doi.org/10.1210/jc.2014-2684
23. C. Virili, P. Trimboli, F. Romanelli, M. Centanni, Liquid and
softgel levothyroxine use in clinical practice: state of the art.
Endocrine 54(1), 3–14 (2016). https://doi.org/10.1007/s12020-
016-1035-1.
24. P. Fallahi, S.M. Ferrari, A. Antonelli, In patients with subclinical
hypothyroidism while in therapy with tablet L-T4, the liquid L-T4
formulation is more effective in restoring euthyroidism. Endocr.
Pract. 23(2), 170–174 (2017). https://doi.org/10.4158/EP161545.
OR
25. C.P. Lombardi, R. Bocale, A. Barini, A. D’Amore, M. Boscherini,
R. Bellantone, Comparative study between the effects of repla-
cement therapy with liquid and tablet formulations of levothyr-
oxine on mood states, self-perceived psychological well-being and
thyroid hormone profile in recently thyroidectomized patients.
Endocrine 55(1), 51–59 (2017). https://doi.org/10.1007/s12020-
016-1003-9.
26. R. Ferrara, V. lentile, V. Arcoraci, C. Ferrajolo, C. Piccinni, A.
Fontana, S. Benvenga, G. Trifiro, Treatment pattern and frequency
of serum TSH measurement in users of different levothyrox-
ineformulations: a population-based study during the years
2009–2015. Endocrine (2017).10.1007/s12020-017-1242-4
27. G.M. Leggio, T. Incognito, G. Privitera, M.R. Marano, F. Drago,
Comparative bioavailability of different formulations of levo-
thyroxine and liothyronine in healthy volunteers. J. Endocrinol.
Invest. 29(11), RC35–RC38 (2006). 10.1007/BF03349205
28. P. Fallahi, S.M. Ferrari, I. Ruffilli, A. Antonelli, Reversible nor-
malisation of serum TSH levels in patients with autoimmune
atrophic gastritis who received L-T4 in tablet form after switching
to an oral liquid formulation: a case series. BMC. Gastroenterol.
16, 22 (2016). https://doi.org/10.1186/s12876-016-0439-y
29. M.G. Santaguida, C. Virili, S.C. Del Duca, M. Cellini, I. Gatto, N.
Brusca, C. De Vito, L. Gargano, M. Centanni, Thyroxine softgel
capsule in patients with gastric-related T4 malabsorption. Endo-
crine 49(1), 51–57 (2015). https://doi.org/10.1007/s12020-014-
0476-7
30. D. Ribichini, G. Fiorini, A. Repaci, V. Castelli, L. Gatta, E.
Vaira, R. Pasquali, Tablet and oral liquid Lthyroxineformula-
tion in the treatment of naive hypothyroid patients with Heli-
cobacter pyloriinfection. Endocrine (2016). 10.1007/s12020-
016-1167-3
31. I. Pirola, A.M. Formenti, E. Gandossi, F. Mittempergher, C.
Casella, B. Agosti, C. Cappelli, Oral liquid L-thyroxine (L-t4)
may be better absorbed compared to L-T4 tablets following bar-
iatric surgery. Obes. Surg. 23(9), 1493–1496 (2013). https://doi.
org/10.1007/s11695-013-1015-y
32. P. Fallahi, S.M. Ferrari, S. Camastra, U. Politti, I. Ruffilli, R. Vita,
G. Navarra, S. Benvenga, A. Antonelli, TSH normalization in
bariatric surgery patients after the switch from L-thyroxine in
tablet to an oral liquid formulation. Obes. Surg. 27(1), 78–82
(2017). https://doi.org/10.1007/s11695-016-2247-4
33. S.A. Irving, T. Vadiveloo, G.P. Leese, Drugs that interact with
levothyroxine: an observational study from the thyroid epide-
miology, audit and research study (TEARS). Clin. Endocrinol.82
(1), 136–141 (2015). https://doi.org/10.1111/cen.12559
34. I. Sachmechi, D.M. Reich, M. Aninyei, F. Wibowo, G. Gupta, P.J.
Kim, Effect of proton pump inhibitors on serum thyroid-
stimulating hormone level in euthyroid patients treated with
levothyroxine for hypothyroidism. Endocr. Pract. 13(4), 345–349
(2007). 10.4158/EP.13.4.345
35. C.J. Diskin, T.J. Stokes, L.M. Dansby, L. Radcliff, T.B. Carter,
Effect of phosphate binders upon TSH and L-thyroxine dose in
591
patients on thyroid replacement. Int. Urol. Nephrol. 39(2),
599–602 (2007). https://doi.org/10.1007/s11255-006-9166-6
36. J.W. Dietrich, K. Gieselbrecht, R.W. Holl, B.O. Boehm,
Absorption kinetics of levothyroxine is not altered by proton-
pump inhibitor therapy. Horm. Metab. Res. 38(1), 57–59 (2006).
https://doi.org/10.1055/s-2006-924980
37. S. Ananthakrishnan, L.E. Braverman, R.M. Levin, B. Magnani, E.
N. Pearce, The effect of famotidine, esomeprazole, and ezetimibe
on levothyroxine absorption. Thyroid 18(5), 493–498 (2008).
https://doi.org/10.1089/thy.2007.0381
38. V. Guglielmi, A. Bellia, S. Pecchioli, G. Medea, D. Parretti, D.
Lauro, P. Sbraccia, M. Federici, I. Cricelli, C. Cricelli, F. Lapi, What
is the actual epidemiology of familial hypercholesterolemia in Italy?
Evidence from a national primary care database. Int. J. Cardiol. 223,
701–705 (2016). https://doi.org/10.1016/j.ijcard.2016.08.269
39. V. Guglielmi, A. Bellia, S. Pecchioli, D. Della-Morte, D. Parretti, I.
Cricelli, G. Medea, P. Sbraccia, D. Lauro, C. Cricelli, F. Lapi,
Effectiveness of adherence to lipid lowering therapy on LDL-
cholesterol in patients with very high cardiovascular risk: a real-
world evidence study in primary care. Atherosclerosis 263, 36–41
(2017). https://doi.org/10.1016/j.atherosclerosis.2017.05.018
40. C. Cricelli, G. Mazzaglia, F. Samani, M. Marchi, A. Sabatini, R.
Nardi, G. Ventriglia, A.P. Caputi, Prevalence estimates for
chronic diseases in Italy: exploring the differences between self-
report and primary care databases. J. Public Health Med. 25(3),
254–257 (2003)
41. G. Trifiro, P. Morabito, L. Cavagna, C. Ferrajolo, S. Pecchioli, M.
Simonetti, E. Bianchini, G. Medea, C. Cricelli, A.P. Caputi, G.
Mazzaglia, Epidemiology of gout and hyperuricaemia in Italy
during the years 2005-2009: a nationwide population-based study.
Annrheumdis 72(5), 694–700 (2013). https://doi.org/10.1136/a
nnrheumdis-2011-201254
42. F. Lapi, M. Simonetti, R. Michieli, A. Pasqua, M.L. Brandi, B.
Frediani, C. Cricelli, G. Mazzaglia, Assessing 5-year incidence
rates and determinants of osteoporotic fractures in primary care.
Bone 50(1), 85–90 (2012). https://doi.org/10.1016/j.bone.2011.
09.048
43. G. Giussani, C. Cricelli, F. Mazzoleni, I. Cricelli, A. Pasqua, S.
Pecchioli, F. Lapi, E. Beghi, Prevalence and incidence of epilepsy
in Italy based on a nationwide database. Neuroepidemiology 43(3-
4), 228–232 (2014). https://doi.org/10.1159/000368801
44. P. Sathi, S. Kalyan, C.L. Hitchcock, M. Pudek, J.C. Prior, Pro-
gesterone therapy increases free thyroxine levels--data from a
randomized placebo-controlled 12-week hot flush trial. Clin.
Endocrinol. 79(2), 282–287 (2013). https://doi.org/10.1111/cen.
12128
45. G. Trifiro, F. Parrino, J. Sultana, F. Giorgianni, C. Ferrajolo, E.
Bianchini, G. Medea, S. Benvenga, I. Cricelli, C. Cricelli, F. Lapi,
Drug interactions with levothyroxine therapy in patients with
hypothyroidism: observational study in general practice. Clin.
Drug. Investig. 35(3), 187–195 (2015). https://doi.org/10.1007/
s40261-015-0271-0
46. B.R. Haugen, Drugs that suppress TSH or cause central hypo-
thyroidism. Best Pract. Res. Clin. Endocrinol. Metab. 23(6),
793–800 (2009). https://doi.org/10.1016/j.beem.2009.08.003
47. M. Salas, A. Hofman, B.H. Stricker, Confounding by indication:
an example of variation in the use of epidemiologic terminology.
Am. J. Epidemiol. 149(11), 981–983 (1999)
48. L. Romanelli, E. Mhillaj, V. Cuomo, The importance of reporting
unexpected drug failure. J. Pharmacovigil. 4(1), 1–2 (2016).
https://doi.org/10.4172/2329-6887.1000e148
49. D. Pincus, T. Gomes, C. Hellings, H. Zheng, J.M. Paterson, M.M.
Mamdani, D.N. Juurlink, A population-based assessment of the
drug interaction between levothyroxine and warfarin. Clin. Phar-
macol. Ther. 92(6), 766–770 (2012). https://doi.org/10.1038/clpt.
2012.171
592
50. P.N. Taylor, A. Iqbal, C. Minassian, A. Sayers, M.S. Draman, R.
Greenwood, W. Hamilton, O. Okosieme, V. Panicker, S.L. Tho-
mas, C. Dayan, Falling threshold for treatment of borderline
elevated thyrotropin levels-balancing benefits and risks:
evidence from a large community-based study. JAMA Intern Med
174(1), 32–39 (2014). https://doi.org/10.1001/jamainternmed.
2013.11312
51. Y. Ingrasciotta, J. Sultana, F. Giorgianni, A.P. Caputi, V. Arcor-
aci, D.U. Tari, C. Linguiti, M. Perrotta, A. Nucita, F. Pellegrini, A.
Fontana, L. Cavagna, D. Santoro, G. Trifiro, The burden of
nephrotoxic drug prescriptions in patients with chronic kidney
Endocrine (2018) 59:585–592
disease: a retrospective population-based study in Southern Italy.
PLoS. ONE. 9(2), e8907 (2014). https://doi.org/10.1371/journal.
pone.0089072
52. W. Willett, An overview of issues related to the correction of non-
differential exposure measurement error in epidemiologic studies.
Stat. Med. 8(9), 1031–1040 (1989). discussion 1033–1071
53. I. Donangelo, G.D. Braunstein, Update on subclinical hyperthyr-
oidism. Am. Fam. Physician. 83(8), 933–938 (2011)
54. A.M. Formenti, G. Mazziotti, R. Giubbini, A. Giustina, Treatment
of hypothyroidism: all that glitters is gold? Endocrine 52(3),
411–413 (2016). https://doi.org/10.1007/s12020-016-0882-0