Drug malabsorption is a potential concern after bariatric surgery. We present four case reports of hypothyroid patients who were well replaced with thyroxine tablets to euthyroid thyrotropin (TSH) levels prior to Roux-en-Y gastric bypass surgery. These patients developed elevated TSH levels after the surgery, the TSH responded reversibly to switching from treatment with oral tablets to a liquid formulation

Agosti B

Cappelli C

Casella C

Formenti AM

Gandossi E

Mittempergher F

Pirola I

PubMed

Ilenia Pirola

Anna M. Formenti

Elena Gandossi

Francesco Mittempergher

Claudio Casella

Barbara Agosti

Carlo Cappelli

Springer - Publisher Connector

Oral Liquid l-Thyroxine (l-T4) May Be Better Absorbed Compared to l-T4 Tablets Following Bariatric Surgery

PIROLA, Ilenia

CAPPELLI, Carlo

CASELLA, Claudio

Archivio istituzionale della ricerca - Università di Brescia

BRIEF COMMUNICATIONOral Liquid L-Thyroxine (L-T4) May Be Better AbsorbedCompared to L-T4 Tablets Following Bariatric SurgeryIlenia Pirola & Anna M. Formenti & Elena Gandossi &Francesco Mittempergher & Claudio Casella &Barbara Agosti & Carlo CappelliPublished online: 4 July 2013# The Author(s) 2013. This article is published with open access at Springerlink.comAbstract Drug malabsorption is a potential concern afterbariatric surgery. We present four case reports of hypothy-roid patients who were well replaced with thyroxine tabletsto euthyroid thyrotropin (TSH) levels prior to Roux-en-Ygastric bypass surgery. These patients developed elevatedTSH levels after the surgery, the TSH responded reversiblyto switching from treatment with oral tablets to a liquidformulation.Keywords Severe obesity . Roux-en-Y gastric bypasssurgery . L-thyroxine . Liquid formulation . AbsorptionIntroductionGlobal demand for bariatric surgery has increased dramati-cally in the past decade [1]. This procedure refers to varioussurgical techniques employed for achieving weight loss.Drug malabsorption is a potential postsurgical concern,particularly after diversionary procedures, for many reasons.Nearly all oral agents are maximally absorbed in the smallintestine, which is bypassed in several bariatric procedures.Delayed gastric emptying, diminished opportunity for mucosalexposure, and changes in drug dissolution and solubilityresulting from alterations in intestinal pH are additional factorsthat may potentially impair drug absorption [2, 3].Levothyroxine (L-T4) is an effective replacement therapyfor patients with hypothyroidism or suppressive therapy aftersurgical removal of thyroid cancer [4, 5]. Absorption of L-T4is reduced when it is ingested concomitantly with other drugsor with coffee [6] and also when gastric pH is altered byautoimmune gastritis or by infection with Helicobacter py-lori [7, 8]. Evidence for diminished L-T4 absorption has beenreported in patients after bariatric surgery [3, 9, 10].We observed an increase in serum thyrotropin (TSH)levels after bariatric surgery in a previously euthyroid patientreceiving L-T4 in tablet form. This condition was reversiblyresolved by switching to the same dose in a liquid oralformulation. We subsequently identified three additional sta-ble hypothyroid patients submitted to bariatric surgery, whonormalised serum TSH after switching from tablets to theoral liquid formulation.Patients and MethodsSerum concentrations of free thyroxine (fT4; normal range,8.0–19.0 pg/mL; analytical sensitivity, 1 pg/mL; intra andinter-assay coefficient of variation, 2.4 and 6.8%, respectively),free triiodothyronine (fT3; normal range, 2.4–4.7; analyticalsensitivity, 0.35 pg/mL; intra and inter-assay coefficient ofvariation, 4.6 and 6.5 %, respectively), and TSH (normal range,0.4–4.5 mIU/L; analytical sensitivity, 0.004 mlU/L; intra andinter-assay coefficient of variation, 2.5 and 5.7 %, respectively)were measured by means of immunochemoluminiscent assaysusing an automated analyser (Immulite 2000, DPC Cirrus, LosAngeles, CA, USA) employing commercial kits (DiagnosticProducts Corporation, Los Angeles, CA, USA).I. Pirola :A. M. Formenti : E. Gandossi :C. Cappelli (*)Department of Clinical and Experimental Sciences, Endocrine andMetabolic Unit, Clinica Medica, University of Brescia,1 Medicina Spedali Civili di Brescia, Piazzale Spedali Civili n1,25100 Brescia, Italye-mail: cappelli@med.unibs.itF. Mittempergher : C. CasellaDepartment of Department of Molecular and TranslationalMedicine, 1st Division of General Surgery, University of Brescia,Brescia, ItalyB. AgostiDiabetic Unit, Spedali Civili di Brescia, Place Spedali Civili 1,25100 Brescia, ItalyOBES SURG (2013) 23:1493–1496DOI 10.1007/s11695-013-1015-yCase ReportsPatient 1 was a 64-year-old obese Caucasian woman (BMI,44.6 kg/m2) who was receiving stable substitutive therapyfor hypothyroidism due to Hashimoto’s thyroiditis. In No-vember 2009, she underwent bariatric surgery (Roux-en-Ygastric bypass). She was euthyroid receiving 200 μg L-T4daily in tablet form. One year after surgery, she had lost35 kg, but her thyroid hormone profile revealed subclinicalhypothyroidism. We changed the formulation from oral tab-lets to liquid, maintaining the same dosage. After 2 months,her TSH levels were in the normal range and she felt better.To confirm the presumed relationship between oral formula-tion and TSH normalisation, L-T4 was re-administered at thesame dosage in tablet form. Once again, serum TSH increased(Table 1). The patient verified medication compliance.Patient 2 was a 33-year-old obese Caucasian woman(BMI, 45.8 kg/m2) who was receiving stable replacementtherapy after a thyroidectomy for benign multinodular goitre.In September 2010, she underwent Roux-en-Y gastric by-pass. She had been euthyroid receiving 150 μg daily of L-T4tablets. One year after surgery, she had lost 41 kg. At thattime, her serum TSH was 12.1 mIU/L, fT4 was 10.2 pg/mL,and fT3 was 3.2 pg/mL. Based on our previous experiencewith patient 1, we decided to switch from tablets to an oralliquid formulation, maintaining the same dosage also in thiscase. Euthyroidism was restored after 2 months. Once again,when L-T4 was re-administered in tablet form at the samedosage, serum TSH levels increased (Table 1).Patient 3 was a 29-year-old obese Caucasian woman(BMI, 45.1 kg/m2) who was receiving stable replacementtherapy for Hashimoto’s thyroiditis. In December 2010, sheunderwent Roux-en-Y gastric bypass surgery. She was eu-thyroid receiving 200 μg of L-T4 daily in tablet form. Oneyear after surgery, she had lost 39 kg; however, her thyroidprofile had worsened. Also in this case, we introduced anoral liquid formulation, maintaining the same dosage, andobtained a rapid normalisation of TSH levels. Once again,when L-T4 was re-administered in tablet form at the samedosage, serum TSH increased (Table 1).Patient 4 was a 39-year-old obese Caucasian woman(BMI, 43.9 kg/m2) who was on stable replacement therapyfor Hashimoto’s thyroiditis. In January 2011, she underwentRoux-en-Y gastric bypass surgery. She was euthyroid receiv-ing 150 μg of L-T4 daily in tablet form. One year aftersurgery, she had lost 34 kg. At that time, her serum TSHwas 17.2mIU/L, fT4was 11.0 pg/mL, and fT3was 2.8 pg/mL.We replaced her L-T4 tablets with an oral liquid formulation,maintaining the same dosage. Euthyroidism was restored after2 months. Once again, re-administration of L-T4 at the samedosage in tablet form resulted in an increase in serum TSH(Table 1).DiscussionAll four of the hypothyroid patients described in this reporthad a substantial decrease in serum TSH levels afterswitching from treatment with thyroxine tablets to an oralliquid formulation.After oral administration, approximately 60–90 % of an L-T4 dose is absorbed within 3 h of ingestion. A majority of theabsorption takes place in the jejunum and ileum [11]. Absorp-tion 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 themorning before breakfast [12]. Benvenga et al., clearlyshowed that ingesting L-T4 treatment with coffee, or withwater followed by coffee within a few minutes, results in poorTSH response in many patients [13]. Moreover, concomitantassumption of a number of drugs and other substances canreduce 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 bariatricsurgery, particularly after diversionary procedures. All of ourTable 1 Thyroid parameters measured at the indicated times in four patients who underwent bariatric surgery between 2009 and 2011. Patients werereceiving oral L-T4 in either tablet or liquid form as indicatedBefore surgery L-T4 in tabletform12 Months after surgery L-T4 intablet form14 Months after surgeryL-T4 inliquid form17 Months after surgery L-T4 intablet formPatient L-T4 (μg) TSH fT4 fT3 L-T4 (μg) TSH fT4 fT3 L-T4 (μg) TSH fT4 fT3 L-T4 (μg) TSH fT4 fT31 200 4.2 12.7 3.1 200 18.1 10.4 2.9 200 1.5 12.9 3.8 200 36.7 9.8 3.02 150 3.1 12.9 3.3 150 12.1 10.2 3.2 150 1.9 13.5 4.0 150 24.7 10.4 3.23 200 3.9 11.7 3.7 200 20.4 10.2 3.3 200 0.6 13.5 3.2 200 17.7 10.2 3.14 150 3.6 10.9 3.2 150 17.2 11.0 2.8 150 2.4 11.9 3.2 150 15.3 10.1 3.1L-T4 levothyroxine, TSH thyrotropin, fT4 free tyroxine, fT3 free triiodothyronin1494 OBES SURG (2013) 23:1493–1496patients underwent Roux-en-Y gastric bypass (RYGB), whichbypasses almost the entire stomach. It consisted of transectingthe upper stomach, creating a small proximal gastric pouch,which is then anastomosed to the proximal jejunum. A recentreview by Padwall et al. points out that highly lipophilic drugsand/or those that undergo enterohepatic recirculation, such aslevothyroxine, have the greatest potential for malabsorptionafter bariatric surgery [3].Our observations are at odds with the findings of Rubioet al., who compared the mean absorption of L-T4 tablets in15 obese patient candidates for RYGB bypass surgery, withthat of 15 patients who had undergone such surgery 2–3-months previously and found no significant difference be-tween groups regarding L-T4 absorbance [6]. There are somedifferences between our observations and this study. Patientsin this study had undergone surgery 2–3 months prior toassessment, while in all four of our patients, the aberrantthyroid parameters were apparent 12 months after surgery. Inaddition, three of our four patients were receiving L-T4 forhypothyroidism due to Hashimoto’s thyroiditis, while all 15patients who underwent surgery in the study by Rubio et al.had thyroid nodular disease. Indeed, the authors pointedto altered L-T4 absorption in some patients as a reasonto monitor thyroid function parameters carefully afterRYGB in patients on stable L-T4 treatment [6]. Inagreement with Azizi et al. and Bevan et al. [9, 10],the serum TSH levels in our patients increased afterbypass surgery, suggesting a malabsorption of L-T4.Interestingly, TSH levels normalised after switchingfrom tablets to liquid oral formulation, and both fT4and fT3 increased into the normal range. Consistent witha hypothesis of reduced absorption of tablets, TSH levelsreturned to high-normal 2 months after re-introduction of tablets.To our knowledge, this is the first report showing revers-ible normalisation of serum TSH levels in patients submittedto bariatric surgery who received L-T4 in tablet form afterswitching to an oral liquid formulation. At present, we do nothave an explanation for this observation. The fact that thechange from tablets to oral formulation normalised serumTSH levels, and that switching back to tablets caused thyro-tropin levels to worsen, leads us believe that absorption ofthyroxine is greater with oral liquid formulations in ourpatients after bariatric surgery.Patients with impaired acid secretion require a higher doseof thyroxine, suggesting that normal gastric acid secretion isnecessary for effective absorption of L-T4 [7]. Drug dissolu-tion and solubility may be altered by restrictive proceduresthat increase gastric pH in the newly created stomach pouch.This may occur in gastric bypass or gastroplasty, in whichthe new gastric pouch is partitioned from acid-producingcells in the remaining stomach [3]. Recently, Saracenoet al. have shown that the liquid formulation of L-T4 is anextremely effective means to circumvent the problem ofincomplete absorption of the L-T4 of caused by proton pumpinhibitor-induced increases in gastric pH [20]. It is conceiv-able that this formulation could also circumvent the pHalteration resulting from gastric bypass.Another hypothesis is that the presence of alcohol (only inthe liquid formulation) could play a key role in thyroxineabsorption. Indeed, oral mucosal drug delivery is known asan alternative method for systemic drug delivery that offersseveral advantages over both injectable and enteral methods[21]. Because the oral mucosa is highly vascularised, drugsthat are absorbed through the oral mucosa directly enter thesystemic circulation, bypassing the gastrointestinal tract[21]. Consistent with this hypothesis, we would expect tosee more rapid pharmacokinetics if oral liquid thyroxine canbe absorbed by oral mucosa. Further studies are needed toclarify this intriguing point.Finally, it is important to underline that liquid T4 formu-lation (Tirosint® fiala monouso, IBSA Farmaceutici Italia) istoday available only in Italy, and that at the dosage of 100 μgdaily is more expensive that tablets (0.06 than 0.33 Euro,respectively, daily).In summary, we report four patients submitted tobariatric surgery, in whom oral liquid L-thyroxine in-duced a reversible normalisation of thyrotropin levels.It is likely that patients affected by condition thatimpair L-T4 absorption (e.g., bariatric surgery) couldbenefit from a liquid formulation.Open AccessThis article is distributed under the terms of the CreativeCommons Attribution License which permits any use, distribution, andreproduction in any medium, provided the original author(s) and thesource are credited.References1. Samuel I, Mason EE, Renquist KE, Huang YH, et al. Bariatricsurgery trends: an 18-year report from the International BariatricSurgery Registry. Am J Surg. 2006;192(5):657–62.2. Miller AD, Smith KM. Medication and nutrient administrationconsiderations after bariatric surgery. Am J Health Syst Pharm.2006;63(19):1852–7.3. Padwal R, Brocks D, Sharma AM. A systematic review of drugabsorption following bariatric surgery and its theoretical implica-tions. Obes Rev. 2010;11(1):41–50.4. Pacini F, Castagna MG. Approach to and treatment of differentiatedthyroid carcinoma. Med Clin N Am. 2012;96(2):369–83.5. Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, andmanagement. Med Clin N Am. 2012;96(2):203–21.6. Rubio IG, Galrão AL, Santo MA, et al. Levothyroxine absorptionin morbidly obese patients before and after Roux-En-Y gastricbypass (RYGB) surgery. Obes Surg. 2012;22(2):253–8.7. Centanni M, Gargano L, Canettieri G, et al. Thyroxine in goiter,Helicobacter pylori infection, and chronic gastritis. N Engl J Med.2006;354(17):1787–95.8. Checchi S, Montanaro A, Pasqui L, Ciuoli C, De Palo V, et al.L-thyroxine requirement in patients with autoimmuneOBES SURG (2013) 23:1493–1496 1495hypothyroidism and parietal cell antibodies. J Clin EndocrinolMetab. 2008;93(2):465–9.9. Azizi F, Belur R, Albano J. Malabsorption of thyroid hor-mones after jejunoileal bypass for obesity. Ann Intern Med.1979;90(6):941–2.10. Bevan JS, Munro JF. Thyroxine malabsorption following intestinalbypass surgery. Int J Obes. 1986;10(3):245–6.11. Benvenga S, Bartolone L, Squadrito S, et al. Delayed intestinalabsorption of levothyroxine. Thyroid. 1995;5(4):249–53.12. Lamson MJ, Pamplin CL, Rolleri RL, et al. Quantitation of asubstantial reduction in levothyroxine (T4) absorption by food.Thyroid. 2004;14:876. abstract.13. Benvenga S, Bartolone L, Pappalardo MA, et al. Altered intestinalabsorption of L-thyroxine caused by coffee. Thyroid. 2008;18(3):293–301.14. Liel Y, Sperber AD, Shany S. Nonspecific intestinal adsorption oflevothyroxine by aluminum hydroxide. Am J Med. 1994;97(4):363–5.15. Sherman SI, Tielens ET, Ladenson PW. Sucralfate causes malab-sorption of L-thyroxine. Am J Med. 1994;96(6):531–5.16. Campbell NR, Hasinoff BB, Stalts H, et al. Ferrous sulfate reducesthyroxine efficacy in patients with hypothyroidism. Ann InternMed. 1992;117(12):1010–3.17. Northcutt RC, Stiel JN, Hollifield JW, et al. The influence ofcholestyramine on thyroxine absorption. J Am Med Assoc.1969;208(10):1857–61.18. Singh N, Weisler SL, Hershman JM. The acute effect of calciumcarbonate on the intestinal absorption of levothyroxine. Thyroid.2001;11(10):967–71.19. Chiu AC, Sherman SI. Effects of pharmacological fiber supple-ments on levothyroxine absorption. Thyroid. 1998;8(8):667–71.20. Saraceno G, Vita R, Trimarchi F, et al. A liquid formulation of L-thyroxine (L-T4) solves problems of incomplete normalization/suppression of serum TSH caused by proton pump inhibitors(PPI) on conventional tablet formulations of L-T4. Presented atEuropean Society of Endocrinology ICE/ECE 2012 Florence,Italy. Endocrine Abstracts 29:P1626 [abstract].21. Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery: clinicalpharmacokinetics and therapeutic applications. Clin Pharmacokinet.2002;41(9):661–80.1496 OBES SURG (2013) 23:1493–1496

Oral liquid L-thyroxine (L-t4) may be better absorbed compared to L-T4 tablets following bariatric surgery.

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Obesity Surgery

http://dx.doi.org/10.1007/s11695-013-1015-y

Oral liquid L-thyroxine (L-t4) may be better absorbed compared to L-T4 tablets following bariatric surgery.

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