EMPATHY: A New Tool for Identifying the Most Suitable Thyroxine Formulation in Hypothyroid Patients

Introduction

Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed. Even though combined thyroxine (T4)/triiodothyronine (T3) therapy has been recommended by some authors (1), the current gold standard treatment consists of thyroid hormone replacement therapy with levothyroxine (LT4) (2). Based on body weight, hypothyroid patients with minimal endogenous thyroid function typically require LT4 doses of 1.6–1.8 μg per kilogram of actual body weight, although some studies estimate higher doses of 2.0–2.1 μg/kg for some patient groups (3 –5).

Absorption of LT4 is highly variable; it is generally assumed that 70% of ingested LT4 is absorbed (6). Thyroxine absorption takes place in the duodenum and the upper tract of the small intestine, is maximal when the stomach is empty, and is affected by a number of gastrointestinal disorders, such as impaired gastric acid secretion due to Helicobacter pylori–related gastritis, atrophic gastritis, ingestion of drugs, dietary fibers, and herbal remedies (6 –11). Other malabsorptive disorders, such as celiac disease and inflammatory bowel disease, or previous bariatric surgery, can also increase the requirement for LT4 by reducing the fraction of the ingested dose that is absorbed (12 –14). Moreover, food allergies or intolerances may lead to chronic bowel inflammation with consequent impairment of LT4 absorption (15).

In the majority of cases, failure to achieve the thyrotropin (TSH) target during LT4 therapy is due to a lack of adherence to prescribed medication (13,16), and in about 40% of cases to factors affecting absorption (13,17).

During the past few years, various LT4 formulations (tablets, soft-gel capsules, and liquid solution) have become available for clinical use, although not in all countries (18). In particular, the use of “non-solid” LT4 formulations (liquid preparation or soft-gel capsules) has been proposed for the management of those hypothyroid patients who are at risk of insufficient adherence to the therapy, or who present an altered absorption of LT4 tablets because of interfering factors or gastrointestinal disease (12,19 –21).

Questionnaires to assess adherence to therapies are available and have also been adapted for patients with hypothyroidism (22,23). On the contrary, there are no available tools to detect malabsorption disorders, knowledge of which may help in choosing the most appropriate thyroxine formulation.

The aim of the present study was to develop and validate a questionnaire for detecting disorders of the gastrointestinal tract in hypothyroidism. In particular, the study evaluated whether this tool may help in selecting the most appropriate thyroxine formulation and obtaining a more rapid achievement of the TSH target, with a decreased need for dose adjustments.

Methods

Three hundred (100 males) newly diagnosed hypothyroid patients affected by isolated autoimmune thyroiditis were consecutively recruited from those attending the Endocrinology and Metabolic Diseases Unit of the University Hospital of University of Campania “L. Vanvitelli” and randomly assigned (1:1 allocation) to complete the Evaluation of Malabsorption in PATients with HYpothyroidism (EMPATHY) questionnaire (150 patients, 50 males and 100 females, group 1) or to a control group (150 patients, 50 males and 100 females, group 2). The choice of LT4 formulation was made on the basis of the questionnaire answers (group 1) or the history (group 2).

Inclusion criteria were age <60 years, TSH level >10 mIU/L, and low/normal free T3 and free T4 levels. According to European Thyroid Association guidelines, patients with these characteristics need treatment with LT4 (1,24). Exclusion criteria were previous thyroidectomy for thyroid cancer, central hypothyroidism, diabetes, obesity, current LT4 therapy, pregnancy, or concomitant drug intake interfering with LT4 absorption.

All patients gave their written informed consent to be enrolled into this study, which was approved by the Local Institutional Review Board (Ethics Committee of the University of Campania “Luigi Vanvitelli”—A.O.R.N. “Ospedale dei Colli”). All participants underwent a medical history and a physical examination at the initial visit, including thyroid palpation and ultrasound. Patients in group 1 completed an EMPATHY questionnaire at the first visit.

EMPATHY consists of seven questions (Fig. 1). It allows the evaluation of lactose and gluten intolerance, some other allergies (nickel and cornstarch), and histamine, citric acid, and alcohol intolerance. The first three questions (q1–q3; Fig. 1A) investigate whether the patient had been previously diagnosed with gastrointestinal disorders, such as food allergy or intolerance, gastritis, gastroesophageal reflux disease, H. pylori–related infection, or bowel disease. In these conditions, as well as other conditions associated with impaired gastric acidity, a non-solid formulation is preferable (4,25). The next two questions (q4 and q5) investigate the presence of particular dietary habits (vegetarian, vegan) or high intake of soya. Soya interferes highly with thyroxine absorption, and the intake of a liquid formulation is indicated (26). The sixth question (q6) aims to identify patients with alcohol intolerance, abstinent subjects, or patients with a history of alcohol addiction, who may be prohibited from formulations containing alcohol (Tirosint^® oral solution, IBSA; Tirosint^® drops, IBSA) even at very low concentrations, and that for this reason could be poorly compliant with treatment. Tablets or soft-gel formulation are preferable in these patients.

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FIG. 1.

(A) Seven questions of the Evaluation of Malabsorption in PATients with HYpothyroidism (EMPATHY) questionnaire. (B) For q7, if the patient refers to problems with at least two foods from the same group, this indicates a possible allergy/intolerance.

The seventh question (q7) screens for some allergies or intolerances unknown to the patients, indicated in Figure 1B. If the patients report gastrointestinal disorders after eating a particular category of foods (at least two), an allergy/intolerance is suspected. In the case of nickel allergy, histamine, or gluten intolerance, as well as in the presence of malabsorption, a non-solid formulation is preferable. If the answers suggest an intolerance to lactose, citric acid, or cornstarch allergy, formulations containing these substances as excipients should be avoided. In particular, these substances are present in tablet formulations (Table 1).

Serum thyroid hormones and TSH were measured at enrollment and every two months for six months; antiperoxidase and antithyroglobulin antibodies were evaluated at the first visit to confirm the diagnosis of thyroiditis. For each patient, the thyroxine dose (1.6 μg/kg/day) was calculated and slowly titrated. Patients were advised to take the therapy as prescribed, since missing three or more daily LT4 doses in a month would have led to exclusion from the study. Patients were informed about the correct way to take the drug, which they had to record daily in a diary.

For each patient, the number of the dose adjustments during the six months of the study and the time to achieve the TSH target range was recorded. TSH concentrations between 0.4 and 2.5 mIU/L were considered as appropriate biochemical control of the thyroid dysfunction (1).

TSH levels were measured with a radioimmunoassay (DiaSorin, intra-assay CV: 1.9%); free T3 and free T4 levels were measured using the SPALT method (DiaSorin, intra-assay CV: 2.8% and 2.0%, respectively).

Differences between frequencies were calculated using the chi-square test or Fisher's exact test. Differences between groups were evaluated by Student's t-test or rank-sum test, as appropriate. A p-value of <0.05 was considered statistically significant.

Results

The demographic and clinical characteristics of the participants in the study are summarized in Table 2. All patients had increased titers of antiperoxidase and/or antithyroglobulin antibodies; most of them had sonographic features consistent with autoimmune thyroiditis. There were no significant differences between the two groups of patients for any clinical and demographic characteristics.

On the basis of the answers to the EMPATHY questionnaire, an allergy/intolerance was suspected in 45/150 (30%) patients in group 1 (Table 2). The numbers of each formulation assigned in the two groups are depicted in Figure 2. In both groups, most patients (60% in group 1 and 64% in group 2) were on tablet treatment. All patients were highly compliant with therapy, and no patient recorded more than two failures to take the therapy. A significantly higher LT4 final dose was found in group 2 (148 ± 33 μg/day) compared to group 1 (136 ± 28 μg/day; p = 0.003).

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FIG. 2.

Distribution of different thyroxine formulations in two groups. Group 1: patients completing EMPATHY questionnaire. Group 2: control group (patients not partaking in the questionnaire).

The mean TSH concentration was significantly lower in group 1 compared to group 2 at the second and third visits (p = 0.002 and p = 0.001, respectively); no significant difference was recorded at sixth months (p = 0.12; Table 3).

A significantly higher number of dose adjustments was found in group 2 compared to group 1 (272 vs. 203; p < 0.001). There were more than two dose adjustments during the six-month period in 21/150 (14%) patients in group 1 and in 42/150 (28%) patients in group 2 (p = 0.005; Table 4). It was found that 6/150 (4%) patients in group 1 and 17/150 (11%) patients in group 2 (p = 0.03) did not achieve the TSH target range after six months, showing a TSH concentration ≥2.5 mIU/L (Table 4). On the contrary, the achievement of the TSH target (TSH <2.5) was already observed by the second visit in 91/150 (60%) patients in group 1 and in 62/150 (41%) in group 2 (p = 0.001; Table 4).

Discussion

The results of this study show that the EMPATHY questionnaire may be useful in clinical practice, allowing better personalization of thyroxine replacement therapy, with more rapid achievement of the TSH target and less need for subsequent dose adjustments.

EMPATHY may be useful not only for identifying a gastrointestinal disorder affecting absorption already known by the patient, but also for suspecting a food allergy or intolerance unknown to the patient. Food allergy is an adverse immune response, and food intolerance is a non-immunological reaction that can be caused by enzyme deficiencies, pharmacological agents, and naturally occurring substances (15). Food intolerance is caused by certain food ingredients, carbohydrates (mainly lactose and fructose), proteins (gluten), and biogenic amines (histamine), which impair digestion (27,28). On one hand, an allergy or intolerance may lead to chronic bowel inflammation with consequent absorption impairment and then a reduction in the thyroxine dose absorption; on the other hand, by introducing a particular thyroxine formulation, there is also a small risk of excipient-induced gastrointestinal issues.

Absorption disorders have to be considered in those cases in which hypothyroidism persists, despite large amounts of LT4 (6 –11,29). The common approach to managing patients with unusual thyroxine need is to increase the dose of LT4 until the targeted TSH levels are achieved. This approach can increase the risk of prolonged exposure to supra-therapeutic doses of LT4, which could potentially increase the chances of adverse outcomes (30). By identifying the best formulation for each patient, EMPATHY allows the achievement of the TSH target with lower thyroxine doses and perhaps a lower risk of adverse outcomes. Of note, a recent review and meta-analysis of studies published on this issue until 2018 emphasized that patients treated with liquid LT4 formulations achieved the TSH target with lower doses because of better absorption (21). Thus, it can be the case that patients with suboptimal TSH values while treated with LT4 in tablet form may achieve the TSH target with a liquid formulation of LT4 without changing the dose.

Moreover, patients completing EMPATHY seem to achieve the TSH target with a decreased need for subsequent dose adjustments. As reported in a recent consensus statement, repeated adjustments of LT4 can also increase the cost of treatment, as frequent office visits and laboratory tests are required to determine and maintain the desired dose (30). Malabsorption can drastically increase management costs. As reported in some simulations, in a hypothyroid American population (633,204 subjects) with malabsorption due to the intake of ferrous sulfate or calcium carbonate, the cost of three or five TSH assays is estimated to be about $56,988360–$94,980,600 (31). This study found that the rate of patients who did not reach the target TSH range after six months was decreased by 7% in group 1. It is thought that this reduction may result in a reduction of management costs if one would consider a larger cohort of hypothyroid patients because these patients need fewer office visits and laboratory tests for further dose adjustments.

In both groups, most patients (60% and 64%, respectively) were on tablet treatment, but the results on dose adjustments and control of disease suggest that the treatment could be better individualized and that the choice of thyroxine formulations was improved for patients in group 1. The study also found a significantly higher number of patients using soft-gel formulation in group 1 than in group 2, and a lower number using liquid formulation in group 1 than in group 2, because of a better identification of patients who need to avoid alcohol among those completing the questionnaire (group 1 patients).

EMPATHY has some limitations. It allows only a suspicion of gastrointestinal disorders rather than a diagnosis. While the information from the questionnaire may help an appropriate thyroxine formulation to be chosen, other specific diagnostic exams remain mandatory when gastrointestinal diseases are suspected. Second, the sample is not large enough to allow generalization of the results, and other studies involving more patients remain necessary to confirm the utility of this tool.

The results of this study demonstrate important differences between patients completing EMPATHY and those not completing the questionnaire. Pending further validation, EMPATHY appears to provide a useful tool in clinical practice, allowing better personalization of LT4 replacement therapy, a more rapid attainment of the TSH target, and a decreased need for subsequent dose adjustments.