In Treating for Hypothyroidism, Do You Consider Malabsorption Issues?

In patients with Hashimoto’s thyroiditis, adjusting for levothyroxine dose and formulation should be informed by EMPATHY trial findings to attain TSH range and achieve optimal patient compliance.

with Maria Del Pilar Brito, MD

Determining the correct dose and route of administration, particularly when prescribing levothyroxine (LT4) to patients with newly diagnosed hypothyroidism, often requires repeated adjustments.

The recent expansion in formulations of levothyroxine, including tablets, soft gel capsules, and liquid solutions, has afforded clinicians greater leeway in selecting the most favorable delivery route to boost patient compliance.1

Equally important, the newer formulations of levothyroxine offer distinct pharmacokinetics that may be a consideration in patients with conditions that may adversely affect bioavailability of LT4 delivered in the standard oral pill.

When prescribing levothyroxine, issues of malabsorption, dose, formulation should be considered.

Dosing Strategy Influenced by Levothyroxine Bioavailability

Dosing Strategy May be Improved with Consideration of Impaired Levothyroxine Absorption  

Failure to achieve the targeted thyrotropin (TSH) level may arise as a result of poor compliance with the recommended treatment (60% of cases) or malabsorption (40%).1 However, short of taking a complete medical history, there are currently no available tools to help clinicians identify patients with gastrointestinal absorption disorders, particularly in patients with undiagnosed underlying conditions.

To address this deficit, a group of endocrinologists developed the Evaluation of Malabsorption in PATients with Hypothyroidism (EMPATHY) questionnaire.2 The EMPATHY questionnaire is comprised of seven statements that assess for:

  • Prior diagnoses of gastrointestinal disorders
  • Lactose intolerance
  • Gluten sensitivity
  • Allergies, particularly nickel and cornstarch
  • Histamine, citric acid, and alcohol intolerances

The researchers noted that patients with conditions associated with impaired gastric acidity may be best managed with a non-solid levothyroxine formulation; those with a high intake of soy, including vegetarians and vegans, might need a liquid solution, as soy interferes with thyroxine absorption.

Patients with a history of alcohol abuse/addiction or an regular intake of alcohol would benefit from an alcohol-free formulation. Allergies can also inform treatment selection, as tablets may include lactose, citric acid, or cornstarch as excipients, so suggesting softgel capsules (Levothyroxine sodium, Tirosint) or liquid is preferable.3

Patients may not be aware that they have food intolerances that might interfere with thyroxine absorption. The investigators therefore formulated questions to identify patients with any of these concerns.2

Randomized Trial to Evaluate the EMPATHY Questionnaire

This study involved randomizing 300 patients (100 males) who were newly diagnosed with hypothyroidism into two groups: one group received the EMPATHY questionnaire and the other provided their medical history to inform treatment selection.2

Serum thyroid hormone and TSH levels were measured at baseline (study enrollment) and at three and five months. In addition, antiperoxidase and antithyroglobulin antibodies were measured at the study outset to confirm the diagnosis of thyroiditis.

The investigators compared the number of dose adjustments initiated during the six months of the study and the time required to achieve TSH target range for the two groups. TSH levels were measured with a radioimmunoassay; free T3 and free T4 levels were measured using the SPALT method.2

A significantly greater number of dose adjustments were necessary in patients who were prescribed medications based on their reported medical history (P < 0.001), and twice as many patients needed more than two dose adjustments in the control group as compare with the EMPATHY group (28% vs 14%, P = 0.005).2

Similarly, nearly three times as many patients in the control group did not achieve the TSH target range at six months (11% vs 4%). The investigators concluded that this tool may be useful not only to calculate individual thyroxine replacement therapy dosing but also in identifying suspected food allergies or intolerances unknown to the patient.

Intriguing Insights on Levothyroxine Prescribing Need Replication

“Although the study was well done, with appropriate processes, methods, and patient selection, the patient population was too small in order to be able to interpret the findings as a stand-alone study, or to make generalizations to the wider population,” said Maria Del Pilar Brito, MD, assistant professor of Medicine, Endocrinology, Diabetes and Bone Disease at Mount Sinai Beth Israel Hospital, in New York City, in reviewing the study and its implications for EndocrineWeb.

Although nearly one-third of the patients in the EMPATHY group were shown to have an allergy or intolerance, “there was a low percentage of patients who had any of the specific metabolic concerns.” Out of 150 participants: 4 were shown to have lactose intolerance, 10 had a nickel allergy, another 4 presented with a gluten intolerance, and 18 had a high alcohol intake.2

Dr. Brito’s raised another concern: “the patients in this study were not receiving the same LT4 dosages from the same company in the three different routes of administration.” This is a problem as there can be a substantial amount of variation in concentrations across different company formulations; optimally, a study such as this would use standardized concentrations from the same company to eliminate that variability.

Thyroid hormone replacement in traditional tablet formulations requires higher stomach acidity (ie, a low pH) in order to be fully and optimally absorbed. As such, patients are usually instructed to take the tablets first thing in the morning when gastric acidity is at its the highest, and told to avoid taking an antacid or ingest other products that might otherwise interfere with absorption, such as vitamins or specific medications, for at least an hour afterward.

Common Medications with Potential to Reduce LT4 Absorption3

  • Calcium carbonate
  • Ferrous sulfate
  • Orlistat
  • Bile acid sequestrants
  • Proton pump inhibitors
  • Antacids

Consider Overall Clinical Fitness of Individual in Selecting Levothyroxine Formulation

“The new liquid formulation does not appear to be influenced as much by alterations in stomach acidity, food, vitamins, or antacids, etc.” Consequently, said Dr. Brito, “there is a very low likelihood of having a malabsorption problem outside of someone with perhaps uncontrolled or not yet diagnosed celiac disease/gluten sensitivity.”

However, Dr. Brito indicated that there are some clinical situations in which a liquid formulation might be recommended, such as for those patients who have a fear of taking pills, have swallowing issues, or are being tube-fed. In addition, “I would consider switching from a tablet to liquid formulation if I had already corrected for all other possible causes of absorption issues, and I am still not getting my patient to target [TSH] levels.”

The Italian research team did not respond to a request for comment on their findings but wrote that “validation of EMPATHY provides endocrinologists with a useful tool in clinical practice, permitting a better personalization of LT4 replacement therapy, a more rapid attainment of the target TSH levels, and a decreased need for dose adjustments after initiating therapy.”2

In summary, Dr. Brito said, this is a well-done albeit small study that warrants additional trialing– either repeated through further study to garner a sufficient number of patients with malabsorption problems or in a much larger patient population that is more reflective of the general population.

Continue Reading:
Levothyroxine: More Leeway In Timing of Administration?
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