All four of the hypothyroid patients described in this report had a substantial decrease in serum TSH levels after switching from treatment with thyroxine tablets to an oral liquid formulation.
After oral administration, approximately 60–90 % of an l
-T4 dose is absorbed within 3 h of ingestion. A majority of the absorption takes place in the jejunum and ileum [11
]. Absorption is maximal when administered on an empty stomach, reflecting the importance of gastric acidity in the process. For this reason, l
-T4 is usually taken with water in the morning before breakfast [12
]. Benvenga et al., clearly showed that ingesting l
-T4 treatment with coffee, or with water followed by coffee within a few minutes, results in poor TSH response in many patients [13
]. Moreover, concomitant assumption of a number of drugs and other substances can reduce l
-T4 absorption; these include aluminium hydroxide [14
], sucrafate [15
], ferrous sulphate [16
], cholestyramine [17
], calcium carbonate [18
] and fibre supplements [19
Drug malabsorption is a potential concern after bariatric surgery, particularly after diversionary procedures. All of our patients underwent Roux-en-Y gastric bypass (RYGB), which bypasses almost the entire stomach. It consisted of transecting the upper stomach, creating a small proximal gastric pouch, which is then anastomosed to the proximal jejunum. A recent review by Padwall et al. points out that highly lipophilic drugs and/or those that undergo enterohepatic recirculation, such as levothyroxine, have the greatest potential for malabsorption after bariatric surgery [3
Our observations are at odds with the findings of Rubio et al., who compared the mean absorption of l
-T4 tablets in 15 obese patient candidates for RYGB bypass surgery, with that of 15 patients who had undergone such surgery 2–3 months previously and found no significant difference between groups regarding l
-T4 absorbance [6
]. There are some differences between our observations and this study. Patients in this study had undergone surgery 2–3 months prior to assessment, while in all four of our patients, the aberrant thyroid parameters were apparent 12 months after surgery. In addition, three of our four patients were receiving l
-T4 for hypothyroidism due to Hashimoto’s thyroiditis, while all 15 patients who underwent surgery in the study by Rubio et al. had thyroid nodular disease. Indeed, the authors pointed to altered l
-T4 absorption in some patients as a reason to monitor thyroid function parameters carefully after RYGB in patients on stable l
-T4 treatment [6
]. In agreement with Azizi et al. and Bevan et al. [9
], the serum TSH levels in our patients increased after bypass surgery, suggesting a malabsorption of l
-T4. Interestingly, TSH levels normalised after switching from tablets to liquid oral formulation, and both fT4 and fT3 increased into the normal range. Consistent with a hypothesis of reduced absorption of tablets, TSH levels returned to high-normal 2 months after re-introduction of tablets.
To our knowledge, this is the first report showing reversible normalisation of serum TSH levels in patients submitted to bariatric surgery who received l-T4 in tablet form after switching to an oral liquid formulation. At present, we do not have an explanation for this observation. The fact that the change from tablets to oral formulation normalised serum TSH levels, and that switching back to tablets caused thyrotropin levels to worsen, leads us believe that absorption of thyroxine is greater with oral liquid formulations in our patients after bariatric surgery.
Patients with impaired acid secretion require a higher dose of thyroxine, suggesting that normal gastric acid secretion is necessary for effective absorption of l
]. Drug dissolution and solubility may be altered by restrictive procedures that increase gastric pH in the newly created stomach pouch. This may occur in gastric bypass or gastroplasty, in which the new gastric pouch is partitioned from acid-producing cells in the remaining stomach [3
]. Recently, Saraceno et al. have shown that the liquid formulation of l
-T4 is an extremely effective means to circumvent the problem of incomplete absorption of the l
-T4 of caused by proton pump inhibitor-induced increases in gastric pH [20
]. It is conceivable that this formulation could also circumvent the pH alteration resulting from gastric bypass.
Another hypothesis is that the presence of alcohol (only in the liquid formulation) could play a key role in thyroxine absorption. Indeed, oral mucosal drug delivery is known as an alternative method for systemic drug delivery that offers several advantages over both injectable and enteral methods [21
]. Because the oral mucosa is highly vascularised, drugs that are absorbed through the oral mucosa directly enter the systemic circulation, bypassing the gastrointestinal tract [21
]. Consistent with this hypothesis, we would expect to see more rapid pharmacokinetics if oral liquid thyroxine can be absorbed by oral mucosa. Further studies are needed to clarify this intriguing point.
Finally, it is important to underline that liquid T4 formulation (Tirosint® fiala monouso, IBSA Farmaceutici Italia) is today available only in Italy, and that at the dosage of 100 μg daily is more expensive that tablets (0.06 than 0.33 Euro, respectively, daily).
In summary, we report four patients submitted to bariatric surgery, in whom oral liquid l-thyroxine induced a reversible normalisation of thyrotropin levels. It is likely that patients affected by condition that impair l-T4 absorption (e.g., bariatric surgery) could benefit from a liquid formulation.