levothyroxine ( l - t4 ) is used worldwide as replacement therapy for patients with hypothyroidism , and for the last few years it has been the third most commonly dispensed therapy in the united states .
synthetic l - t4 as a therapeutic agent was first used in the 1950s and was widely adopted as the primary agent for thyroid hormone replacement , replacing the natural desiccated thyroid extract that had been used over the previous 50-year period . although replacement therapy with levothyroxine has been prescribed for more than 60 years and is generally considered straightforward , cross - sectional surveys of patients on treatment with levothyroxine demonstrate that between 40% and 48% are either overtreated or undertreated [ 3 , 4 ] .
firstly , a number of factors may interfere with intestinal absorption of l - t4 , including food , dietary fibre , coffee , drugs , gastric or intestinal resection , and disease . as a result
, current guidelines recommend that l - t4 is taken in a fasting state at least 30 minutes before breakfast [ 68 ] .
secondly , it is not always reliable to follow medical advice , especially for drug therapy ; this is especially relevant for l - t4 therapy as a significant number of patients have problems in postponing their breakfast by 3060 minutes to ensure that they take l - t4 in the fasting state . in the therapeutic scenario the recent introduction of nontablet l - t4 formulations , such as liquid and soft gel capsules , would seem to raise doubts as to this recommendation .
the results of a recent randomized , double - blind , placebo - controlled crossover trial showed that a liquid l - t4 formulation can be ingested during each patient 's normal breakfast , mixed with tea , coffee , milk , cappuccino , orange juice , and so forth , thus potentially improving therapeutic compliance .
this study , the  titi  study ( tirosint-versus - tiche study , ibsa italia ) , looked to extend these findings by investigating whether an l - t4 soft gel capsule formulation could also be safely and effectively administered to stable euthyroid patients during each patient 's normal breakfast without any malabsorption .
eligible patients were selected by a search in the database for those treated and followed up at the thyroid unit of the department of clinical and experimental sciences , university of brescia , italy . eligibility ( search ) criteria were as follows : ( a ) treatment of hypothyroidism with liquid l - t4 ( ibsa farmaceutici italia srl . , lodi , italy ) ingested during each patient 's normal breakfast ; ( b ) stable levothyroxine replacement over the last 6 months ; ( c ) complete personal medical history ; and ( d ) details of current drug therapy and any previous therapy . in order to avoid any possible confounders ( i.e. , the need to increase l - t4 therapy in patients affected by hashimoto 's thyroiditis during the study span ) we enrolled only patients who had previously undergone total thyroidectomy for proven benign goitre .
all participants had to maintain the same breakfast habits and any ongoing therapy for the entire period of the study .
all patients were assessed for thyroid - stimulating hormone ( tsh ) , free t4 ( ft4 ) , and free t3 ( ft3 ) levels and were switched from liquid l - t4 to the soft gel capsule formulation at the same dosage of l - t4 , ingested during each patient 's normal breakfast .
serum concentrations of tsh , ft4 , and ft3 were once again established after six months .
all patients gave their informed consent to participate in the study , conducted in accordance with the declaration of helsinki .
serum concentrations of ft4 ( normal range 8.019.0  pg / ml , analytical sensitivity 1  pg / ml ) , ft3 ( normal range 2.44.7 , analytical sensitivity 0.35  pg / ml ) , and tsh ( normal range 0.44.5  miu / l , analytical sensitivity 0.004  miu / l ) were measured using a fully automated architect i2000 analyzer ( abbott diagnostics , abbott park , il , usa ) based on chemiluminescent magnetic immunoassay .
tsh , ft4 , and ft3 levels distribution levels were nonnormally distributed and were not normalized by the usual procedures of data transformation ; in these cases results are presented as median with minimum and maximum values .
comparisons between continuous variables were performed by paired samples t - test or related samples by the wilcoxon signed rank test , as appropriate .
of the 2371 assessed patients with hypothyroidism , 60 ( 51 females and 9 males , aged 47.7  11.2 years ) were eligible for the inclusion criteria and were enrolled for the study .
all patients were euthyroid based on test results conducted 6 months before recruitment whilst receiving stable liquid l - t4 therapy ingested with breakfast ( mean dosage 106.25  24.28  g / day ) .
a detailed description of breakfast composition , particularly related to insoluble fibres and/or soya milk , was obtained in each subject ( table 1 ) .
the thyroid hormonal profiles during administration of liquid l - t4 six months before recruitment , at enrolment and after 6 months ' treatment with l - t4 soft gel capsules , are shown in table 2 .
there were no differences in tsh levels at the three different time points , but during treatment with the soft gel capsule formulation ft3 and ft4 levels were significantly lower than those found 6 months before recruitment and at enrolment with the liquid l - t4 formulation .
a subgroup analysis was conducted on the last 30 consecutive patients using data after three months of treatment with l - t4 soft gel capsules ( table 3 ) .
there were no significant differences in hormone levels between 6 months before recruitment , enrolment , and at 3 months .
significant reductions in ft3 and ft4 levels were observed between 3 and 6 months ' treatment with l - t4 soft gel capsules whereas there was a slight increase in tsh value .
the main finding of this study is that both the liquid and soft gel capsule formulations of l - t4 can be taken with breakfast .
priority should however be given to the liquid l - t4 formulation in those patients where even a small change in ft4 and ft3 levels is to be avoided .
current guidelines for the treatment of hypothyroidism recommend ingesting levothyroxine in the fasting state 6030 minutes before breakfast or at bedtime , at least three hours after the evening meal , for optimal and consistent absorption [ 68 ] .
this recommendation is based on study data demonstrating that concomitant ingestion of food [ 1215 ] , fibre , soya products , and coffee   is associated with higher serum tsh values in hypothyroid subjects treated with l - t4 as compared with the fasting state . taking l - t4 with coffee , or with water followed by coffee within a few minutes , results in a poor tsh response in many patients .
the recent introduction of new nontablet formulations of l - t4 , such as soft gel capsules and a liquid , could resolve this problem .
in one small study of hypothyroid patients , vita et al . observed that the absorption of a soft gel preparation of l - t4 ( tiche capsules , ibsa , switzerland ) was not impaired by taking it with coffee .
the same authors also reported that the problem of incomplete absorption of l - t4 caused by proton pump inhibitor - induced increases in gastric ph was not observed with the l - t4 soft gel formulation .
demonstrated that there is therapeutic equivalence in liquid l - t4 administration at breakfast or 10  min beforehand .
we have previously observed that taking l - t4 at 30 minutes before having breakfast was not associated with alterations in optimal tsh , ft4 , and ft3 concentrations in a group of patients taking their dose of a liquid l - t4 formulation ( tirosint , ibsa , italy ) with coffee .
more recently , we clearly demonstrated in a randomized , placebo - controlled double - blind crossover trial that the thyroid hormone profiles are almost identical after the administration of the same dose of oral liquid l - t4 either with breakfast or in the fasting state ( 30 minutes before breakfast ) .
, no previous study has made comparisons between soft gel capsule and liquid formulations of l - t4 taken at breakfast time .
the clinical relevance of the significant reduction in ft4 and ft3 serum levels after switching from liquid to soft gel capsule l - t4 is not clear .
nevertheless , further analysis of data on the last 30 patients would appear to indicate a progressive reduction in ft4 and ft3 levels after the switchover as time passed . at three months from switching over from liquid to soft gel capsule l - t4 , tsh ,
ft4 , and ft3 levels were superimposable on those found at recruitment , but reductions were seen over the next 3 months of therapy ( i.e. , by 6 months ) .
the tsh had again slightly increased but the change was not of statistical significance . based on these findings , it would be reasonable to assume that absorption of the soft gel capsule l - t4 formulation gradually diminishes as time passes when ingested with breakfast .
a longer follow - up during soft gel capsule treatment could yield further information on the trend of thyroid hormonal profile and the clinical significance of the hormonal changes demonstrated by this study .
for this reason , large longitudinal prospective studies are needed to clarify this important issue . in conclusion ,
the results of this study suggest that , in general , both the liquid and soft gel capsule formulations of l - t4 can be taken with breakfast .
priority should however be given to the liquid l - t4 formulation in those patients where even small changes in ft4 and ft3 levels need to be avoided , such as those receiving suppressive therapy for thyroid cancer and/or cardiopathic patients receiving substitutive l - t4 therapy .
 
 background . 
 recently , it has been shown that liquid l - t4 formulation can be ingested with breakfast . 
 this study looked to extend these findings by investigating whether a soft gel capsule formulation of l - t4 could also be ingested at breakfast time . methods . 
 60 patients ( 1865  yrs ) , previously submitted to thyroidectomy for proven benign goitre in stable euthyroidism receiving liquid l - t4 therapy ingested with breakfast , were enrolled . 
 tsh , ft4 , and ft3 levels were assessed in all the patients who were switched from liquid l - t4 to a soft gel capsule formulation at the same dosage of l - t4 . 
 after 6 months , tsh , ft4 , and ft3 levels were determined again . 
 results . 
 there were no differences in tsh levels , but ft3 and ft4 levels during treatment with the soft gel capsule were significantly lower than those at enrolment with the liquid l - t4 formulation ( tsh median ( min  max ) : 1.9 ( 0.54.0 ) versus 2.2 ( 0.54.5 ) miu / l , ft3 : 2.5 ( 2.43.1 ) versus 2.7 ( 2.43.3 ) pg / ml , p < 0.05 , and ft4 : 9.9 ( 8.013 ) versus 10.6 ( 8.613.8 ) pg / ml , p < 0.0001 ) . conclusion . 
 both liquid and soft gel formulations of l - t4 can be taken with breakfast 
 . however , liquid l - t4 would be the preferred formulation for patients in whom even small changes in ft4 and ft3 levels are to be avoided . 