Roberto Vita

The administration of L-thyroxine as soft gel capsule or liquid solution

Introduction: Levothyroxine (l-T4) is the mainstay of treating hypothyroidism. The tablet is the traditional formulation of l-T4. Tablet l-T4 malabsorption results from either hindered gastric dissolution of the tablet or binding of l-T4 by sequestrants in the intestinal lumen. Areas covered: This review provides an overview of the pharmacokinetics of l-T4 formulations available in the market: the tablet, the soft gel capsule and the oral solution. We review literature on the new formulations and anticipate the areas of future research. Expert opinion: Failure of l-T4 treatment to reach target serum thyroid-stimulating hormone levels generally prompts the physicians to increase l-T4 daily dose. In vitro studies have shown that the soft gel capsule releases the active ingredient more consistently at varying pH than the tablet. In addition, in vivo studies have confirmed the in vitro data and have demonstrated that both the soft gel capsule and the liquid formulation are capable to solve tablet l-T4 malabsorption caused by certain drugs, bariatric surgery or coffee. These new formulations may be attractive also for patients who cannot/do not want to change their (improper) habits of l-T4 ingestion. Finally, the oral solution l-T4 could be suitable for patients who cannot swallow the solid formulations.

The association of other autoimmune diseases in patients with autoimmune thyroiditis: Review of the literature and report of a large series of patients.

We have evaluated prospectively the prevalence of other autoimmune disorders in outpatient clinic in 3069 consecutive patients with diagnosed chronic autoimmune thyroiditis (AT), with respect to two age- and sex-matched control groups: a) a control group of 1023 subjects, extracted from a random sample of the general population without thyroid disorders; b) 1023 patients with non-toxic multinodular goiter extracted from the same random sample of the general population, with similar iodine intake. The results of our study demonstrate a significant increase of the prevalence of autoimmune disorders in AT patients (with respect to both controls), for the following diseases: chronic autoimmune gastritis (CAG), vitiligo (Vit), rheumatoid arthritis, polymialgia rheumatica (Polym), celiac disease, diabetes, sjogren disease, multiple sclerosis, systemic lupus erythematosus, sarcoidosis, alopecia, psoriathic arthritis, systemic sclerosis, and HCV-related cryoglobulinemia. While the statistical analysis reached near the significance for Addisons disease and ulcerative colitis. Interestingly, the association of three autoimmune disorders was observed almost exclusively in AT patients, and the most frequent associations were AT+CAG+Vit and AT+CAG+Polym. We suggest that patients with AT who remain unwell, or who develop new not specific symptoms (despite adequate treatment) should be screened for other autoimmune disorders, avoiding the delay in the diagnosis of these disorders.

Switching Levothyroxine From the Tablet to the Oral Solution Formulation Corrects the Impaired Absorption of Levothyroxine Induced by Proton-Pump Inhibitors

CONTEXT Proton-pump inhibitors (PPIs) impair tablet levothyroxine (LT4) intestinal absorption by increasing the gastric pH and decreasing LT4 dissolution in the stomach. OBJECTIVE The purpose of this study was to verify whether a liquid formulation of LT4 would correct LT4 malabsorption induced by PPIs. DESIGN This was a prospective observational cohort study. The study was conducted from 2012 to 2013, and the mean duration of the follow-up was 23.7 ± 11.9 weeks. SETTING The study was conducted in a tertiary university hospital outpatients clinic. PATIENTS Upon informed consent, we recruited 24 consecutive adult patients (18 women and 6 men), who took LT4 for replacement (n = 14) or suppressive purposes (n = 10) and who had absorption of tablet LT4 impaired by PPIs. INTERVENTION The 24 patients were switched from the tablet to the oral solution LT4 at the same daily dose. MAIN OUTCOME MEASURES Significantly lower mean TSH levels were seen with the oral solution than with the tablet as were significantly greater rates of serum TSH less than or equal to the specified cutoff values (replacement [REP] group) or ≤ 0.10 mU/L (suppressive [SUP] group) with the oral solution than with the tablet. RESULTS Serum TSH was lower with the oral solution than with the tablet formulation (REP group, 1.7 ± 1.0 mU/L vs 5.4 ± 4.3, P < .0001; SUP group, 0.1 ± 0.3 mU/L vs 2.1 ± 2.7, P < .0001). In the REP group, the rate of TSH values of ≤ 4.12 or ≤ 2.5 mU/L was 29 of 30 (96.7%) or 24 of 30 (80.0%) postswitch but only 17 of 36 (47.2%) or 9 of 36 (25.0%) preswitch (P < .0001). In the SUP group, the rate of serum TSH values of ≤ 0.10 mU/L was 26 of 35 (74.3%) postswitch but 0 of 22 (0%) preswitch (P < .0001). CONCLUSIONS These data demonstrate the continued absorption of liquid LT4 despite the increased gastric pH due to PPI therapy.

Thyroid dysfunctions induced by tyrosine kinase inhibitors

Introduction: Recently, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anticancer therapy. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do cause significant side effects including fatigue and hypertension. In addition, thyroid dysfunction is a well-known adverse effect of TKI. Areas covered: This review provides a comprehensive assessment of TKI-induced thyroid dysfunctions by sunitinib, sorafenib, pazopanib, imatinib, dasatinib, nilotinib, vandetanib, axitinib, motesanib and tivozanib. Furthermore, the potential mechanisms that result in this toxicity, the clinical impact of thyroid dysfunction in these patients and the controversies regarding treatment with thyroid hormone (TH) therapy are evaluated. Expert opinion: Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and may necessitate treatment. Potential benefits in developing thyroid dysfunction and potential harm in treating it necessitate controlled studies. Finally, if treatment is pursued, appropriate dosing and timing of TH replacement will require prospective clinical evaluation.

Tablet Levothyroxine (L-T4) Malabsorption Induced by Proton Pump Inhibitor; A Problem that was Solved by Switching to L-T4 in Soft Gel Capsule

OBJECTIVE To report a patient in whom the impaired absorption of tablet levothyroxine (L-T4) due to a proton pump inhibitor (PPI) use was corrected by switching the patient to the soft gel capsule. METHODS A woman with Hashimotos thyroiditis-associated hypothyroidism (serum thyroid-stimulating hormone [TSH] 6.8-9.6 mU/L) had been treated with tablet L-T4 (100 μg/day). Because she used to take pantoprazole just before L-T4 in the morning, TSH failed to normalize (4.4-6.5 mU/L). Thus, the daily dose had been progressively increased to 125 and 150 μg/day, with serum TSH levels of 2.4 and 0.6 mU/L, respectively. RESULTS While maintaining pantoprazole, we switched the tablet L-T4 (150 g/day) to a soft gel capsule (125 μg/day; Tirosint® capsule, IBSA, Lugano, Switzerland) and after 2 months, to 100 μg/day. Serum TSH was lower than under the equivalent regimens with the tablet: 0.5 versus 2.4 mU/L (125 μg/day) and 2.4 versus 4.4 to 6.5 mU/L (100 μg/day). Upon switching back to the tablet (100 μg/day), serum TSH increased to 3.2 and 4.7 mU/L and then dropped to 2.7-3.0 mU/L when the dose was increased to 125 μg/day. We also acutely evaluated the intestinal absorption of L-T4 by administering 600 μg LT4 as a tablet or soft gel capsule while maintaining pantoprazole. Pharmacokinetic indices showed better and faster absorption for the soft gel capsule versus tablet (area under the curve [AUC]0-4h = 16,240 vs. 10,960 nmol/L x 4 hours, maximum absorption [Cmax] = 108 vs. 73 nmol/L, and time of maximum absorption [Tmax] = 120 minutes vs. 180 minutes). CONCLUSION Confirming in vitro studies conducted by other authors, the soft gel capsule L-T4 is negligibly affected by changes in gastric pH compared to tablet L-T4.

Thyroid nodules and thyroid autoimmunity in the context of environmental pollution

Evidence suggests that in most industrialized countries autoimmune disorders, including chronic lymphocytic thyroiditis, are increasing. This increase parallels the one regarding differentiated thyroid cancer, the increment of which is mainly due to the papillary histotype. A number of studies have pointed to an association between chronic lymphocytic thyroiditis and differentiated thyroid cancer. The upward trend of these two thyroid diseases is sustained by certain environmental factors, such as polluting substances acting as endocrine disrupting chemicals. Herein we will review the experimental and clinical literature that highlights the effects of environmental and occupational exposure to polluting chemicals in the development of autoimmune thyroid disease or differentiated thyroid cancer. Stakeholders, starting from policymarkers, should become more sensitive to the consequences for the thyroid resulting from exposure to EDC. Indeed, the economic burden resulting from such consequences has not been quantified thus far.

A patient with stress-related onset and exacerbations of Graves disease.

Background An 18-year-old, nonsmoking woman presented to her general practitioner with a 1-week history of weakness, fatigue, palpitations, nervousness, tremors, insomnia, heat intolerance, and sudden enlargement of a thyroid goiter that had been detected 2 years earlier. The patients symptoms had started shortly after she experienced emotional stress. Diagnostic work-up disclosed an avid radioactive iodine uptake by the goiter. On ultrasound examination, the thyroid gland was enlarged with a diffusely hypoechogenic structure and intense vascularization.Investigations Thyroid scintigraphy with 131I; ultrasonography of the thyroid gland; and measurements of serum free T3, free T4, TSH levels and thyroid autoantibodies, including autoantibodies against thyroglobulin (TgAb), thyroperoxidase (TPOAb) and TSH receptor (TRAb).Diagnosis Graves disease, with stress-related onset and subsequent stress-related exacerbations.Management The patient was treated with methimazole to normalize levels of thyroid hormone and thyroid autoantibodies, and with bromazepam to help her cope with stress. The daily dose of methimazole was kept low during pregnancy. Over the 4 year period when the patient was taking methimazole, exacerbations of hyperthyroidism occurred twice: during her first pregnancy and 9 months after her first delivery. On all three occasions, symptoms were preceded by stressful life events. Further exacerbations were avoided by starting bromazepam treatment soon after the patient experienced stressful events.

Oral liquid levothyroxine solves the problem of tablet levothyroxine malabsorption due to concomitant intake of multiple drugs

ABSTRACT Background: Unlike the tablet (TAB) formulation, liquid L-T4 (LIQ) is directly absorbed in the intestine. The aim of this study was to assess whether LIQ was superior to TAB, such that it would overcome the interference induced by co-ingestion of multiple interfering drugs (ID). Methods: In this prospective cohort study, we recruited 11 patients with apparent reduced TAB absorption due to ≥ 2 ID, and switched them to LIQ while maintaining the daily dose and the co-ingestion of the ID. Serum TSH was assayed at least twice every eight weeks. Results: Serum TSH was significantly lower on LIQ compared with TAB (P < 0.0001), in patients who took L-T4 for either replacement (P = 0.002) or TSH-suppression (P < 0.0001). This difference was evident already at the first measurement post-switch (P = 0.008 or P = 0.03). Regardless of the purpose of L-T4 therapy, patients who took two ID had lower serum TSH on LIQ compared with patients who took three ID (P = 0.0006). Interestingly, 2/3 patients who failed to reach target TSH levels while on LIQ took three ID. Conclusions: LIQ overcomes the concurrent interference exerted by the ingestion of multiple ID. In such cases, switching from TAB to LIQ permits patients to reach target TSH within 8 weeks.

Personalization of Targeted Therapy in Advanced Thyroid Cancer

Although generally the prognosis of differentiated thyroid carcinoma (DTC) is good, approximately 5% of people are likely to develop metastases which fail to respond to radioactive iodine, and other traditional therapies, exhibiting a more aggressive behavior. Nowadays, therapy is chosen and implemented on a watch-and-wait basis for most DTC patients. Which regimen is likely to work best is decided on the basis of an individual’s clinical information, but only data referring to outcomes of groups of patients are employed. To predict the best course of therapy, an individual patient’s biologic data is rarely employed in a systematic way. Anyway, the use of not expensive individual genomic analysis could lead us to a new era of patient-specific and personalized care. Recently, key targets that are now being evaluated in the clinical setting have been evidenced in the pathogenesis of these diseases. Some of the known genetic alterations playing a crucial role in the development of thyroid cancer include B-Raf gene mutations, rearranged during transfection/ papillary thyroid carcinoma gene rearrangements, and vascular endothelial growth factor receptor-2 angiogenesis pathways. The development of targeted novel compounds able to induce clinical responses and stabilization of disease has overcome the lack of effective therapies for DTC, which are resistant to radioiodine and thyroid stimulating hormone-suppressive therapy. Interestingly, the best responses have been demonstrated in patients treated with anti-angiogenic inhibitors such as vandetanib and XL184 in medullary thyroid cancer, and sorafenib in papillary and follicular DTC.

Undertreated hypothyroidism due to calcium or iron supplementation corrected by oral liquid levothyroxine

PurposeThe aim of this study was to assess whether oral liquid levothyroxine would correct tablet levothyroxine malabsorption induced by calcium or iron, two sequestrants of levothyroxine.MethodsNineteen adult hypothyroid patients with tablet levothyroxine malabsorption caused by calcium and/or iron supplements were switched from tablet to liquid levothyroxine at the same dose. Primary outcomes were: (1) significantly lower mean serum thyroid-stimulating hormone with the liquid compared with the tablet formulation, and (2) significantly greater rate of serum thyroid-stimulating hormone less than or equal to 4.12 or 2.5 mU/L.The mean follow-up was 25.2 ± 16.5 weeks.ResultsTSH was lower with liquid levothyroxine compared with tablet levothyroxine (7.48 ± 5.8 vs. 1.95 ± 1.3 mU/L, P < 0.001), both in the calcium group (8.74 ± 7.2 vs. 2.15 ± 1.4, P < 0.001) and iron group (8.74 ± 7.2 vs. 1.68 ± 0.9, P < 0.001). Thyroid-stimulating hormone levels ≤4.12 mU/L in all patients, calcium group and iron group were more frequent post-switch (95, 87 and 100%) compared to pre-switch (26, 22 and 29%, P < 0.001), and so were thyroid-stimulating hormone levels ≤2.50 mU/L (66, 59 and 76% compared to 5, 9 and 0%, P < 0.001). The pattern held comparing the first liquid levothyroxine thyroid-stimulating hormone levels and the first tablet levothyroxine thyroid-stimulating hormone levels or the corresponding rates of thyroid-stimulating hormone levels below the target.ConclusionsLiquid levothyroxine is resistant to the sequestration by calcium or iron. The high rate of thyroid-stimulating hormone normalization already at the first check (6–8 weeks) should avoid frequent adjustments in levothyroxine doses and assays of thyroid-stimulating hormone, with consequent financial savings.