Lactose intolerance and levothyroxine malabsorption: a review of the literature and report of a series of patients treated with liquid L-T4 without lactose.

In hypothyroid patients needing large doses of levothyroxine (L-T4) (>1.7-2 µg/kg/day) to reach euthyroidism, lactose intolerance (LI) needs to be excluded, owing to the high prevalence in the population. If LI is present, a lactose-free diet decreases the rate of L-T4 malabsorption. However, an increased requirement of L-T4 is described in patients with LI, which can be beneficially treated using lactose-free L-T4 formulation. The lactose-free liquid L-T4 formulation is able to circumvent LI malabsorption leading to the normalization of thyroid-stimulating hormone (TSH) in patients with subclinical hypothyroidism and long-term stable TSH levels.

Proton Pump Inhibitors Do Not Affect the Bioavailability of a Novel Liquid Formulation of Levothyroxine.

OBJECTIVE: This study evaluates the impact of a representative proton pump inhibitor (PPI) (omeprazole), administered simultaneously or staggered, on the pharmacokinetics of levothyroxine (LT4) solution (Tirosint-SOL). METHODS: This was a randomized, 3-way crossover, comparative bioavailability study in 36 healthy adults under fasting conditions. Omeprazole 40 mg delayed-release capsule was administered once daily from Day 1 to 6 (mornings, Treatment-A; evenings, Treatment-B; none, Treatment-C) to increase and stabilize gastric pH. In the morning of Day 5, a single dose of LT4 solution 600 mcg was administered. Blood samples were collected 0 to 48 hours post-LT4 administration. Noncompartmental pharmacokinetic parameters were calculated for total serum thyroxine using baseline-corrected data. Maximum concentration (Cmax) and area under the concentration-time curve (AUC0-48) were included in an analysis of variance to obtain geometric mean ratios and 90% confidence intervals. RESULTS: For both comparisons (A/C and B/C), geometric mean ratios and 90% confidence intervals for all parameters were within the equivalence boundaries (80%-125%), indicating bioequivalence: for A/C, AUC0-48 98.98% [94%-104%], and Cmax 91.68% [87%-97%]; for B/C, AUC0-48 98.94% [95%-103%], and Cmax 94.90% [90%-100%]. Median Tmax (time associated with Cmax) was similar across treatments. CONCLUSION: This study demonstrated that Tirosint-SOL bioavailability is unaffected by coadministration of a representative PPI, given simultaneously or staggered by about 12 hours, compared to administration of LT4 solution alone. For hypothyroid patients on PPI therapy, administration of LT4 solution may reduce variations in thyroid stimulating hormone levels related to intermittent use of acid-reducing drugs and consequently the need for dose adjustments.

Development and In Vivo Evaluation of Sustained Release Microparticles Loaded with Levothyroxine for Hypothyroidism Treatment.

Hypothyroidism is a chronic condition combated by a daily oral supplementation of levothyroxine. In addition to the need for frequent dosing, oral administration may result in variable absorption of the drug leading to a failure in achieving normal thyroid function. Therefore, the development of a long-acting injectable system capable of delivering the drug is necessary. This work was aimed at developing sustained release microparticles loaded with levothyroxine. The microparticles were produced through the emulsification-solvent evaporation method using 2 grades of biocompatible and biodegradable polyesters: poly(ᴅ,ʟ-lactide-co-glycolide) (PLGA) and poly(ᴅ,ʟ-lactide) (PLA). Both polymers produced microparticles with very similar sizes (1.9 µm) and zeta potential values (around -22.0 mV). However, PLA microparticles had a significantly higher drug loading (6.1% vs. 4.4%, respectively) and encapsulation efficiency (36.8%, vs. 26.1%, respectively) when compared to PLGA counterparts. While both types of microparticles displayed a biphasic release pattern in vitro, a slower rate of release was observed with PLA microparticles. Moreover, a similar biphasic release pattern was found in vivo, with an initial phase of rapid release followed by a slower phase in the subsequent 10 days. These results indicate the possibility of developing levothyroxine loaded polyester microparticles as a potential long-acting thyroid hormone replacement therapy.

Ionic Levothyroxine Formulations: Synthesis, Bioavailability, and Cytotoxicity Studies.

Thyroid diseases affect a considerable portion of the population, with hypothyroidism being one of the most commonly reported thyroid diseases. Levothyroxine (T4) is clinically used to treat hypothyroidism and suppress thyroid stimulating hormone secretion in other thyroid diseases. In this work, an attempt to improve T4 solubility is made through the synthesis of ionic liquids (ILs) based on this drug. In this context, [Na][T4] was combined with choline [Ch]+ and 1-(2-hydroxyethyl)-3-methylimidazolium [C2OHMiM] + cations in order to prepare the desired T4-ILs. All compounds were characterized by NMR, ATR-FTIR, elemental analysis, and DSC, aiming to check their chemical structure, purities, and thermal properties. The serum, water, and PBS solubilities of the T4-ILs were compared to [Na][T4], as well as the permeability assays. It is important to note an improved adsorption capacity, in which no significant cytotoxicity was observed against L929 cells. [C2OHMiM][T4] seems to be a good alternative to the commercial levothyroxine sodium salt with promising bioavailability.

A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.

Effect of oral semaglutide on the pharmacokinetics of thyroxine after dosing of levothyroxine and the influence of co-administered tablets on the pharmacokinetics of oral semaglutide in healthy subjects: an open-label, one-sequence crossover, single-center, multiple-dose, two-part trial.

BACKGROUND: Oral semaglutide comprises the glucagon-like peptide-1 analog, semaglutide, and sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Levothyroxine has similar dosing conditions to oral semaglutide. This trial investigated if oral semaglutide co-administered with levothyroxine affects thyroxine (T4) exposure and if multiple placebo tablets co-administered with oral semaglutide affect semaglutide exposure. RESEARCH DESIGN AND METHODS: In this one-sequence crossover trial, 45 healthy subjects received levothyroxine (600 µg single-dose) alone, or with concomitant SNAC 300 mg or concomitant oral semaglutide 14 mg at steady-state. Subjects also received oral semaglutide 14 mg at steady-state alone or with five placebo tablets once-daily for 5 weeks. RESULTS: A 33% increase in total T4 exposure was observed with levothyroxine/oral semaglutide vs levothyroxine alone, but baseline-corrected maximum concentration (Cmax) was unaffected. SNAC alone did not affect total T4 exposure, whereas Cmax was slightly decreased. A 34% decrease in semaglutide exposure was observed when oral semaglutide was co-administered with placebo tablets, and Cmax also decreased. CONCLUSIONS: Levothyroxine pharmacokinetics were influenced by co-administration with oral semaglutide. Monitoring of thyroid parameters should be considered when treating patients with both oral semaglutide and levothyroxine. Oral semaglutide exposure was influenced by co-administration with multiple tablets, which is addressed in the dosing guidance.

Decreased Expression of Ileal Thyroid Hormone Transporters in a Hypothyroid Patient: A Case Report.

Background: Malabsorption of levothyroxine (LT4) is a common problem faced in clinical practice. It is usually solved, if there are no complexities including gastrointestinal absorption disorder, by taking medicines on an empty stomach and avoiding foods interfering with LT4. Herein we present a rare case of a patient exhibiting malabsorption of LT4 with decreased membranous expression of ileal transporters. Case: The 22-Year-old female presented with sustained hypothyroid status despite medication of 7.8 µg/kg LT4. Medical history and LT4 absorption test (the absorption rate 8.4%) excluded pseudomalabsorption. No organic gastrointestinal disorder was found in the patient by blood chemistry, endoscopies, and abdominal computed tomography scan. The immunohistochemical analysis showed decreased membranous expression of LAT1 and LAT2 in distal ileum and ascending colon in the patient compared to 20 controls who have no thyroid disease. The expression of MCT8 in colon appeared at both nucleus and brush border in the patient, while it was limited to brush border in controls. The expression of other transporters was similar between the patient and controls. Conclusion: The changes of the expression of LAT1 and LAT2 in this patient showing LT4 malabsorption might help to understand the role of intestinal transporters in the absorption of LT4 in humans. The functional relevance of the decrement of LAT1 and LAT2 in this patient remains to be elucidated.

A systematic approach to metabolic characterization of thyroid-disrupting chemicals and their in vitro biotransformants based on prediction-assisted metabolomic analysis.

Thyroid-disrupting compounds (TDCs) are chemicals that modify thyroid gland function and disrupt hormonal homeostasis. Like other endocrine-disrupting chemicals (EDCs), TDCs often show altered activities following post-metabolic modification via endogenous enzymatic reaction. Hence, we developed evaluation system consisting of (1) in vitro metabolic reaction module, (2) high-resolution mass-spectrometry, and (3) human cell-based reporter gene assay. We developed the reaction module using rat S9 fraction where levothyroxine (T4) as a model compound, was subjected to phase-I or phase-I+II biotransformation. The metabolic profiles of the biotransformants were systematically configured based on in-silico prediction of potential products and experimental validation using liquid-chromatography Orbitrap mass-spectrometry. Thyroid agonistic activities of the biotransformants were evaluated by thyroid receptor-mediated stably transfected transcriptional activation assay using hTRE_HeLa cells. Indeed, we detected the increased activities following metabolic conversion of T4 in a dose-dependent manner. Note that the activity by phase-I+II reaction was much greater than by phase-I reaction (3.8-fold increase). Subsequently, we explored metabolic signatures, which potentially contributed to the hyperactivity by phase-I+II reaction. A total of 77 metabolic features were annotated based on the in-silico prediction, which included biotransformants with deiodination and conjugation. The glucuronide-conjugated form was found at the highest fold-increase (970-fold increase) whereas marginal increases were determined in the deiodinized forms (1.6-fold increase in T3 and 2.0-fold increase in rT3). Further, the systematic approach was evaluated and comparably analyzed by the metabolic profiles of bithionol, which is structurally related to T4. Our current result suggested the potential application of in vitro evaluation system to risk assessment of thyroid-disrupting activity.

Patient-Tailored Levothyroxine Dosage with Pharmacokinetic/Pharmacodynamic Modeling: A Novel Approach After Total Thyroidectomy.

Background: After seven decades of levothyroxine (LT4) replacement therapy, dosage adjustment still takes several months. We have developed a decision aid tool (DAT) that models LT4 pharmacometrics and enables patient-tailored dosage. The aim of this was to speed up dosage adjustments for patients after total thyroidectomy. Methods: The DAT computer program was developed with a group of 46 patients post-thyroidectomy, and it was then applied in a prospective randomized multicenter validation trial in 145 unselected patients admitted for total thyroidectomy for goiter, differentiated thyroid cancer, or thyrotoxicosis. The LT4 dosage was adjusted after only two weeks, with or without application of the DAT, which calculated individual free thyroxine (fT4) targets based on four repeated measurements of fT4 and thyrotropin (TSH) levels. The individual TSH target was either <0.1, 0.1-0.5, or 0.5-2.0 mIU/L, depending on the diagnosis. Initial postoperative LT4 dosage was determined according to clinical routine without using algorithms. A simplified DAT with a population-based fT4 target was used for thyrotoxic patients who often went into surgery after prolonged TSH suppression. Subsequent LT4 adjustments were carried out every six weeks until target TSH was achieved. Results: When clinicians were guided by the DAT, 40% of patients with goiter and 59% of patients with cancer satisfied the narrow TSH targets eight weeks after surgery, as compared with only 0% and 19% of the controls, respectively. The TSH was within the normal range in 80% of DAT/goiter patients eight weeks after surgery as compared with 19% of controls. The DAT shortened the average dosage adjustment period by 58 days in the goiter group and 40 days in the cancer group. For thyrotoxic patients, application of the simplified DAT did not improve the dosage adjustment. Conclusions: Application of the DAT in combination with early postoperative TSH and fT4 monitoring offers a fast approach to LT4 dosage after total thyroidectomy for patients with goiter or differentiated thyroid cancer. Estimation of individual TSH-fT4 dynamics was crucial for the model to work, as removal of this feature in the applied model for thyrotoxic patients also removed the benefit of the DAT.

New Formulations of Levothyroxine in the Treatment of Hypothyroidism: Trick or Treat?

Background: Levothyroxine (LT4) as a medication is used by up to 5.3% of the adult population. For optimal efficacy, the traditional tablet formulation (LT4tab) requires that patients avoid concomitant ingestion with food, drinks, and certain medications, as well as excellent patient compliance. Some comorbidities influence bioavailability of LT4 and may mandate repeated dose adjustments. Summary: New LT4 formulations (soft gel [LT4soft] and liquid [LT4liq]) containing predissolved LT4 are claimed to improve bioavailability, presumably by facilitating absorption. Thus, these formulations may well be more suitable than LT4tab for patients whose daily requirements are subjected to variations in bioavailability. Here, we review the evidence and indications for use of new LT4 formulations and highlight areas of uncertainty that are worthy of further investigation. While bioequivalence is established for LT4soft and LT4liq administered to healthy volunteers compared with LT4tab in pharmacokinetic (PK) studies, therapeutic equivalence of the new formulations seems to be different in several clinical settings. Some evidence suggests that new formulations of LT4 may mitigate against the strict requirements relating to concomitant ingestion with food, drinks, and certain medications, which apply to traditional LT4 tablets. The principal indication is in selected patients with disease fluctuations and intermittent therapies with interfering medications, where the need for frequent dose adjustments and office visits may be diminished. Whether the use of LT4soft or LT4liq in patients with impaired gastric acid secretion results in better control of hypothyroidism than LT4tab remains unclear. Conclusions: The evidence in favor of using LT4soft and LT4liq in clinical practice over LT4tab is weak, and the underlying putative PK mechanisms unclear. Additional studies to investigate these potential benefits, define the cost-effectiveness, and understand the PK mechanisms involved with new LT4 formulations are needed.

The Levothyroxine Absorption Test: A Four-Year Experience (2015-2018) at The Mayo Clinic.

Background: Levothyroxine (LT4) is the mainstay of therapy for hypothyroidism. Yet, despite physician efforts at dose titration, some patients remain hypothyroid on LT4 doses in excess of weight-based calculations, a condition known as refractory hypothyroidism. The LT4 absorption test (LT4AT) has been proposed to have utility in these patients by enabling distinction of LT4 malabsorption from pseudomalabsorption, a condition of intentional nonadherence. Given its rare use in clinical practice, we reviewed our institution's experience with the LT4AT to assess its impact on management of refractory hypothyroidism. Methods: We reviewed the charts of 16 patients diagnosed with refractory hypothyroidism and who had completed the LT4AT between January 2015 to January 2019. The primary aim was to determine the utility of this test in distinguishing LT4 malabsorption from pseudomalabsorption. Secondary aims were to determine whether the results of this test impacted physicians' management decisions, as well as to report on clinical outcomes at follow-up. Our LT4AT is a six-hour test wherein patients receive a weight-based dose of LT4 followed by serial measurements of total thyroxine (TT4) and thyrotropin (TSH). Percentage absorption is calculated using the following formula, with normal absorption being ≥60%: [Formula: see text] Results: Percentage absorption was calculated in 13 of 16 patients due to lack of TT4 data for 3 patients. Absorption was impaired in one patient (% absorbed = 0), who had known causes of malabsorption. The remaining 12 patients had normal absorption by hour 4 of the test (% absorption 60-158) in conjunction with upward TT4 trends. Clinical follow-up ranged from 1 to 32 months (median 6.5 months), with 11 patients having follow-up data. Six of these had normal or suppressed TSH values at most recent follow-up, and four had improved but persistent TSH elevations. The one said patient with malabsorption improved with intravenous LT4. Conclusions: The LT4AT can provide valuable information for distinguishing malabsorption from pseudomalabsorption. Our findings support the combined use of calculated percentage absorptions with TT4 trends for at least a four-hour time frame when making determinations regarding absorption.

Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?

In France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox®. In March 2017, at the request of French authorities, a new formulation of Levothyrox® was licensed, with the objective of avoiding stability deficiencies of the old formulation. Before launching this new formulation, an average bioequivalence trial, based on European Union recommended guidelines, was performed. The implicit rationale was the assumption that the two products, being bioequivalent, would also be switchable, allowing substitution of the new for the old formulation, thus avoiding the need for individual calibration of the dosage regimen of thyroxine, using the thyroid-stimulating hormone level as the endpoint, as required for a new patient on initiating treatment. Despite the fact that both formulations were shown to be bioequivalent, adverse drug reactions were reported in several thousands of patients after taking the new formulation. In this opinion paper, we report that more than 50% of healthy volunteers enrolled in a successful regulatory average bioequivalence trial were actually outside the a priori bioequivalence range. Therefore, we question the ability of an average bioequivalence trial to guarantee the switchability within patients of the new and old levothyroxine formulations. We further propose an analysis of this problem using the conceptual framework of individual bioequivalence. This involves investigating the bioavailability of the two formulations within a subject, by comparing not only the population means (as established by average bioequivalence) but also by assessing two variance terms, namely the within-subject variance and the variance estimating subject-by-formulation interaction. A higher within individual variability for the new formulation would lead to reconsideration of the appropriateness of the new formulation. Alternatively, a possible subject-by-formulation interaction would allow a judgement on the ability, or not, of doctors to manage patients effectively during transition from the old to the new formulation.

Recombinant human thyrotropin (rhTSH) versus Levo-thyroxine withdrawal in radioiodine therapy of differentiated thyroid cancer patients: differences in abdominal absorbed dose.

PURPOSE: In DTC patients, 131-radioiodine therapy has routinely been used for many years for thyroid remnant ablation after thyroid surgery. To date, two different strategies can be used to achieve sufficient TSH stimulation on thyroid remnant: (I) Levo-thyroxine withdrawal or (II) rhTSH stimulation. The aim of our study was to compare the abdominal absorbed dose ratio between differentiated thyroid cancer patients who underwent thyroid remnant ablation after either L-T4 withdrawal or rhTSH stimulation. METHODS: We reviewed the records of 63 patients affected by differentiated thyroid cancer. All patients underwent thyroid remnant ablation after either L-T4 withdrawal or rhTSH stimulation. A post-therapy whole-body scan was obtained 5 days after 131-radioiodine therapy. Qualitative and quantitative image analysis was performed. Quantitative analysis was performed by drawing seven regions of interest on the abdomen (anterior and posterior views) to estimate both the activity ratio (AR) and absorbed dose ratio (DR) obtained in patients treated in hypothyroidism or after rhTSH stimulation. RESULTS: The values of the activity and absorbed dose ratios obtained on each abdomen region (liver, stomach, ascending colon, transverse colon, descending colon, rectum, and small intestine) were always higher in patients treated after L-T4 withdrawal than after rhTSH stimulation with p-values of 0.000, 0.000, 0.001, 0.000, 0.022, 0.007, and 0.002, respectively. CONCLUSIONS: DTC patients treated with 131-radioiodine after rhTSH stimulation have lower abdominal radioiodine activity than hypothyroid patients. Our data could be of practical relevance in terms of patient management. The potential impact on rare radioiodine-related gastrointestinal side effects is to be established in specifically designed prospective studies.

Oral levothyroxine therapy postbariatric surgery: Biopharmaceutical aspects and clinical effects.

BACKGROUND: Bariatric surgery can lead to changes in the oral absorption of many drugs. Levothyroxine is a narrow therapeutic drug for hypothyroidism, a common condition among patients with obesity. OBJECTIVE: The purpose of this work was to provide a mechanistic overview of levothyroxine absorption, and to thoroughly analyze the expected effects of bariatric surgery on oral levothyroxine therapy. METHODS: We performed a systematic review of the relevant literature reporting the effects of bariatric surgery on oral levothyroxine absorption and postoperative thyroid function. A PubMed search for relevant keywords resulted in a total of 14 articles reporting levothyroxine status before versus after bariatric surgery. RESULTS: Different mechanisms may support opposing trends as to levothyroxine dose adjustment postsurgery. On the one hand, based on impaired drug solubility/dissolution attributable to higher gastric pH as well as reduced gastric volume, compromised levothyroxine absorption is expected. On the other hand, the great weight loss, and altered set-point of thyroid hormone homeostasis with decreased thyroid-stimulating hormone after the surgery, may result in a decreased dose requirement. CONCLUSIONS: For patients after bariatric surgery, close monitoring of both the clinical presentation and plasma thyroid-stimulating hormone and T4 levels is strongly advised. Better understanding and awareness of the science presented in this article may help to avoid preventable complications and provide optimal patient care.

New Insights on Solid-State Changes in the Levothyroxine Sodium Pentahydrate during Dehydration and its Relationship to Chemical Instability.

Levothyroxine sodium pentahydrate (LEVO) tablets have been on the US market since the mid-twentieth century and remain the most highly prescribed product. Unfortunately, levothyroxine sodium tablets have also been one of the most highly recalled products due to potency and dissolution failures on stability. In 2008, the assay limits were tightened, yet the recalls did not decline, which highlights the serious quality concerns remaining to be elucidated. The aim of the present investigation was to test the hypothesis that the solid-state physical instability of LEVO precedes the chemical instability leading to product failure. The failure mode was hypothesized to be the dehydration of the crystal hydrate, when exposed to certain humidity and temperature conditions, followed by the oxidation of the API through vacated channels. It was previously reported by the authors that LEVO degradation occurred in the presence of oxygen at a low relative humidity (RH). Furthermore, powder X-ray diffractometry shows changes in the crystal lattice of LEVO initially and through the dehydration stages. Storage of LEVO at RT and 40 °C at 4-6% RH for 12 days shows a decrease in d-spacing of the (00 l) planes. Based on a structure solution from the powder data of the dehydrated material, the basic packing motif persists to varying degrees even when fully dehydrated along with disordering. Therefore, the crystal structure changes of LEVO depend on RH and temperature and are now explicable at the structural level for the first time. This exemplifies the dire need for "new prior knowledge" in generic product development.

Pharmacokinetics and Comparative Bioavailability of a Levothyroxine Sodium Oral Solution and Soft Capsule.

A new formulation of levothyroxine sodium has been developed in the form of an oral solution contained in unit-dose ampules. A study has been conducted to compare the bioavailability of levothyroxine sodium oral solution and levothyroxine sodium soft capsule in healthy volunteers under fasting conditions. The rate and extent of absorption of the new levothyroxine solution were also evaluated when administered on dilution in water or directly into the mouth without water. In each period, according to the randomization scheme, subjects were administered single oral doses of either test, as 4 × 150-µg unit-dose ampules, with or without water, or reference, as 4 × 150-µg capsules in a crossover design. Thirty-six subjects were randomized and dosed in this study; of these, 31 completed all study periods. When comparing the solution with the capsule (both products administered with water), the 90% confidence intervals for the ratio of log-transformed values of AUC0-48 and Cmax were within 90.00% and 111.11%, respectively, for baseline-corrected levothyroxine. Moreover, the administration of levothyroxine oral solution without water did not affect the rate and extent of its absorption. In conclusion, levothyroxine oral solution unit-dose ampules were bioequivalent to the levothyroxine capsule when administered with or without water. All formulations were well tolerated, with no major side effects.

Gastrointestinal Malabsorption of Thyroxine.

Levothyroxine, a largely prescribed drug with a narrow therapeutic index, is often a lifelong treatment. The therapeutic efficacy of T4 may be marred by behavioral, pharmacologic, and pathologic issues acting as interfering factors. Despite a continuous search for an optimal T4 treatment, a significant number of patients fail to show a complete chemical and/or clinical response to this reference dose of T4. Gastrointestinal malabsorption of oral T4 represents an emerging cause of refractory hypothyroidism and may be more frequent than previously reputed. In this review, we examine the pharmacologic features of T4 preparations and their linkage with the intestinal absorption of the hormone. We have stressed the major biochemical and pharmacologic characteristics of T4 and its interaction with the putative transporter at the intestinal level. We have examined the interfering role of nutrients, foods, and drugs on T4 absorption at the gastric and intestinal levels. The impact of gastrointestinal disorders on T4 treatment efficacy has been also analyzed, in keeping with the site of action and the interfering mechanisms. Based on the evidence obtained from the literature, we also propose a schematic diagnostic workup for the most frequent and often hidden gastrointestinal diseases impairing T4 absorption.

L-thyroxine malabsorption due to calcium carbonate impairs blood pressure, total cholesterolemia, and fasting glycemia.

PURPOSE: Calcium carbonate was previously shown to interfere with L-thyroxine absorption. To estimate the magnitude of tablet L-thyroxine malabsorption caused by calcium carbonate, with resulting increase in serum thyrotropin (TSH), we performed a cohort study in a referral care center. METHODS: Fifty postmenopausal hypothyroid L-thyroxine-treated women (age 71.7 ± 5.1 years) who added calcium supplementation (600-1000 mg/day) were considered. They were taking L-thyroxine 45-60 min before breakfast (setting 1). After 4.4 ± 2.0 years from initiation of L-thyroxine therapy, they took calcium supplemaentation within 2 h after L-thyroxine taking (setting 2) for 2.3 ± 1.1 years. Hence, we recommended postponing calcium intake 6-8 h after L-thyroxine (setting 3). We evaluated TSH levels, the prevalence of women with elevated TSH (>4.12 mU/L), total cholesterolemia, fasting glycemia, blood pressure, and the prevalence of hypercholesterolemia, hyperglycemia, and hypertension. RESULTS: TSH levels were 3.33 ± 1.93 mU/L versus 1.93 ± 0.51 or 2.16 ± 0.54 comparing setting 2 with setting 1 or 3 (P < 0.001, both). In setting 2, 18% women had elevated TSH versus none in setting 1 or 3 (P < 0.01). Total cholesterolemia, fasting glycemia, systolic, and diastolic blood pressure were also significantly higher in setting 2 compared to settings 1 and 3. For every 1.0 mU/L increase within the TSH range of 0.85-6.9 mU/L, total cholesterolemia, glycemia, systolic, and diastolic blood pressure increased by 12.1, 3.12 mg/dL, 2.31, and 2.0 mmHg, respectively. CONCLUSIONS: Monitoring of hypothyroid patients who ingest medications that decrease L-thyroxine absorption should not be restricted to solely measuring serum TSH.

Sporadic pedunculated duodenal adenomas. Clinical presentations and endoscopic management: a case series.

The prevalence of sporadic duodenal polyps is estimated to be 0.3%-4.6% in patients referred for an upper endoscopy. Most of patients are asymptomatic (66-80%) at the time of diagnosis though bleeding, anemia and abdominal pain are the most commonly reported symptoms. These are related to the polyp's size, location and histological characteristics. We describe three cases of big, pedunculated nonampullary sporadic duodenal polyps (tubulovillous low-grade dysplasia adenomas) located in the second part of the duodenum and characterized by different clinical presentations, managed in our Endoscopic Unit within one year (between 2016 and 2017). Polypectomies were performed, either piece-meal or en-bloc using various endoscopic instruments. In one of our patients (case 1), a delayed bleeding (36 hours after the procedure) occurred eventually managed conservatively with two units of blood transfusion. In the same patient, in the following months after polypectomy, the pre-procedural state of anemia misclassified as Mediterranean anemia has improved with a significant rise of hemoglobin value (14.1g/dl). In a patient who previously underwent a renal transplant (case 2), endoscopy was indicated, based on the positive fecal occult blood test. In another patient (case 3), a big polyp induced pancreatitis since it exerted a strong traction on the duodenal wall during peristaltic movements. The removal of the polyp has led to the resolution of pancreatitis and associated symptoms.

Liquid L-thyroxine versus tablet L-thyroxine in patients on L- thyroxine replacement or suppressive therapy: a meta-analysis.

PURPOSE: To compare the effectiveness of liquid L-T4 (L-thyroxine) and tablet L-T4 in patients on L-T4 replacement or suppressive therapy. METHODS: The Cochrane Library, PubMed, Embase, and Web of Science databases were searched to identify relevant articles. All prospective or randomized controlled studies (RCTs) comparing liquid L-T4 and tablet L-T4 in patients on L-T4 replacement or suppressive therapy were included in the analysis. RESULTS: Overall, the initial search of the four databases identified 1278 published studies; of these, eight studies were ultimately included in the meta-analysis. TSH (thyroid stimulating hormone) levels were significantly suppressed in patients on liquid L-T4 compared with those on tablet L-T4, in patients on L-T4 suppressive therapy with L-T4 malabsorption (Mean Difference (MD) = -2.26, 95% Confidence Interval (CI): -3.59, -0.93; P = 0.0009)). However, liquid L-T4 and tablet L-T4 did not show a statistically significant difference in patients on L-T4 suppressive therapy without malabsorption (MD = 0.08, 95% CI: -0.31, 0.47; P = 0.69). TSH levels were significantly normalized in patients on liquid L-T4 compared with those on tablet L-T4, in Patients on L-T4 replacement therapy with L-T4 malabsorption (MD = -3.20, 95% CI: -5.08, -1.32; P = 0.0009). However, liquid L-T4 and tablet L-T4 did not show a statistically significant difference in patients on L-T4 replacement therapy without malabsorption (MD = 0.91, 95% CI: -0.03, 1.86; P = 0.06). CONCLUSION: Liquid L-T4 is more efficient than tablet L-T4 in patients on L-T4 replacement or suppressive therapy with malabsorption. No significant differences were observed in patients without malabsorption. Further studies should be conducted to verify these findings.