Levothyroxine Absorption Test to Manage Refractory Hypothyroidism

The new clinical tool has been used effectively to identify cases of insufficient LT4 absorption

with Kristin M. Gonzales, MD, and Maria Del Pilar Brito, MD

Given that primary hypothyroidism is a prevalent condition, particularly among women, and suboptimal thyroid replacement may be a likely occurrence, the need to check for and adjust levothyroxine (LT4) dosing for each individual is a vexing clinical challenge.

Furthermore, while most commonly prescribed medications have a single or just two standard doses, thyroid replacement has a narrow therapeutic index with which to treat hypothyroid patients, requiring a more individualized titrated dosing. The precise dosage is determined as much by patient demographics of weight, age, sex, and co-existing medical conditions, as the degree of patient responsiveness to LT4.

Refractory hypothyroidism: an exercise in dosing

It is estimated that 15-20% of patients fail to respond to the initial dose of levothyroxine.1 When the dose of LT4 exceeds 1.9 mcg/kg, yet the thyroxine-stimulated hormone (TSH) level remains at the high end of the reference range, the patient is considered to have refractory hypothyroidism.2,3 As the number of hypothyroid cases rises, the need to understand the mechanisms driving refractory hypothyroidism has become more pressing.

Underlying reasons that patients may be refractory include the small intestines not effectively absorbing LT4 (malabsorption) or because something is preventing LT4 from being fully absorbed (pseudomalabsorption).

Likely causes of pseudomalabsorption are:

  • Drug adherence3
  • Dietary factors
  • Medications
  • Even the way patients store their LT4 at home 

This compounds the difficulty in identifying a therapeutic dose. For refractory patients and their clinicians, adjusting LT4 dose may feel like an exercise in trial and error.

“For patients who continue to have marked elevations in TSH despite escalating doses of LT4, we first recommend an evaluation to assess for causes of persistent TSH elevations. If no cause is identified, and the patient endorses adherence, then performance of the LT4 AT (LT4 absorption test) is reasonable,” Kristen M. Gonzales, MD, of the Mayo Clinic in Rochester, Minnesota, told EndocrineWeb.

Levothyroxine absorption test: an underutilized tool   

Employing the LT4 absorption test as a clinical tool is supported by evidence garnered by a retrospective study5 led by Dr. Gonzales and published in Thyroid. What is apparent—the LT4 absorption test is underutilized and poorly standardized, and is performed with various durations, different LT4 dosing levels, and with a variety of outcomes measures (i.e., total T4 levels vs. free T4 levels).

This study was initiated to demonstrate the expediency of employing the LT4 absorption test, a protocol established by the Endocrine Testing Center at the Mayo Clinic to distinguish malabsorption from pseudomalabsorption.

“In recognizing the limitations of using a non‐isotopic method for making determinations about LT4 absorption, incorporating standardization may minimize any uncertainty pertaining to the accuracy of the test,” said Dr. Gonzales.

Protocol for the LT4 absorption test—three key applications

Before the LT4 absorption test was initiated, patients were instructed to fast overnight and forego any medication, in particular levothyroxine, on the day of testing. Patients received one of three standardized levothyroxine replacement doses based on age and BMI:

  • Patients ages 18-65 years and with a BMI > 40 mg/k2 were given 1500 mcg
  • Patients ages 18-65 years with a BMI < 40 mg/k2 were given 1000 mcg
  • Patients ages 66 years or older (regardless of BMI) received a test dose of 600 mcg

Note that in this study5 there were no patients over the 65 years or under age 21 years.

Total LT4 was measured prior to dosing (at baseline) and again at 1 hour, 2 hours, 3 hours, 4 hours, and 6 hours post-dosing. Thyroid stimulating hormone (TSH) was measured at baseline and again at 6 hours. The percentage of LT4 absorbed was calculated from two measures of total thyroxine (TT4), total LT4 dose, and the volume of distribution (Vd) in the following manner:5

[(peak TT4-baseline TT4) * 10 / total LT4 dose] * Vd * 100 = % LT4 absorption

Note: Peak TT4 and baseline TT4 are measured in micrograms per deciliter (mcg/dL), prompting the conversion of deciliters into liters (L), the standard for Vd; thus, their difference must be multiplied by 10.

Three key elements used by the Endocrine Testing Center that should be standardized across all LT4 absorption tests:

  • Defined test duration
  • Controlled LT4 administration and dosing
  • Using TT4 as the outcome measure

In this study,5 Gonzales et al. reviewed patient records available from the clinical data repository at the Mayo Clinic. Thirteen hypothyroid patients were identified to have been assessed using the LT4 absorption test protocol at the Endocrine Testing Center. They underwent the assessment between 2015 and 2019. Thyroidectomy and Hashimoto’s disease were the two most common causes of hypothyroidism in this cohort.5

Distinguishing pseudomalabsorption from malabsorption

In applying the LT4 absorption test performed under study control conditions, 12 out of 13 patients (including the singular male) had an LT4 absorption greater than or equal to 60%, indicating normal absorption. Within four hours of dosing, all 12 of these patients reached at least normal thyroid levels, although five patients (~41%) experienced peak levels at three hours and three others (25%) showed peak levels at 6 hours.5  

In applying the above formula to calculate LT4 absorption, the authors noted an overestimation (> 100%) of LT4 in several patients at different time points.5 When asked to comment on this outcome, Dr. Gonzales told EndocrineWeb that there are some assumptions made about the volume of distribution that may not correspond directly to LT4 absorption.

“The calculated percent absorption, therefore, is most useful as a dichotomous value in the sense that patients who have a calculated absorption > 60% do seem to have adequate absorption, whereas values below that suggest impairment. Given the limitations of this parameter, however, we suggest interpreting the data from the LT4AT as a whole, factoring in both the percent absorbed and the TT4 trends when making determinations about absorption,” she said.

Thus, for clinicians to realize whether a patient is either above or below the 60% absorption threshold may prove useful in identifying cases of malabsorption, according to Dr. Gonzalez.

For the clinician, the percent absorbed in conjunction with the rate of absorption over the four- to six-hour test may provide additional insight. For the 12 patients with absorption rates greater than 60%, the TT4 increment between baseline and hour four ranged between 5 and 12 mcg/dL. The small sample size precludes any additional analysis of trends; yet, the authors contend that their findings provide sufficient insight to further future investigations.5

TSH levels did not reliably change in conjunction with the level of LT4 absorbed, said Dr. Gonzalez, since 10 of the 12 patients with normal LT4 absorption had lower TSH levels, while the other two patients had minor increases in TSH (less than 10%) despite exceeding 60% absorption threshold in the first two hours of testing.

At hour six, when both TSH and TT4 were measured, these later two subjects had LT4 absorption values of 81% and 158%, with an increase in TSH of 4.2 and 10.7 mIU/L, respectively. The authors suggest that the trend in LT4 absorption across time might also be useful in linking the absorption to TSH measures rather than to percentage of levothyroxine absorbed.6

Also, in one case, LT4 malabsorption (at 0%) was detected at all time points. The clinical records for this patient revealed that she was the only hypothyroid patient with type 1 diabetes and gastroparesis, which would most likely explain the source of her inability to metabolize oral thyroid replacement. 

Take home point for refractory hypothyroid patients — An LT4 absorption value that falls below 60% is indicative that levothyroxine is inadequately absorbed in the intestine. How and when levothyroxine should be taken should be discussed with the patient to ascertain if any actionable behaviors might improve thyroid replacement absorption.

Monitoring is essential for accurate hypothyroid dosing

Follow-up data on ten of the subjects who demonstrated having normal LT4 absorption during testing were available in the clinical data repository. These visits were conducted between one and 32 months (median follow-up 6.5 months) after the initial LT4 absorption test. Nine of these patients showed a decrease in LT4 daily dose and follow-up testing revealed that a majority of study patients (6/10) had slightly suppressed or fell above the desirable range.6

Given the findings, results of the LT4 absorption test suggested that most of the refractory hypothyroid cohort (12/13) most likely suffered from pseudomalabsorption as demonstrated by absorption levels that were calculated to be greater than 60%.

In light of normally expected LT4 absorption, clinical records for the ten follow-up patients suggested that clinicians were reluctant to lower their thyroid replacement doses; all but two patients were still taking an amount of levothyroxine greater than 1.9 mcg/kg at follow-up. According to the researchers, the results of the LT4 absorption test were likely used as an objective tool to guide open discussion on adherence. In fact this may be its greatest value.6

"This is the overriding concern regarding refractory patients: Do patients become refractory because their small intestines are failing to absorb LT4 (malabsorption) or is there some other underlying cause of poor absorption of LT4 (pseudomalabsorption)?” said Dr. Gonzalez.

She said that we speculate that the likeliest causes of pseudomalabsorption stem from:3,4

  • Inconsistent drug adherence
  • Dietary interference
  • Interaction with other medications
  • Storage of LT4 at home

“These factors compound the difficulty that clinicians can be assured their patients are receiving the correct and most effective therapeutic dose,” said Dr. Gonzalez. “When faced with hypothyroid refractory patients, adjusting LT4 dose may feel like an exercise in trial and error, but this effort must be undertaken to address discernable and unknown causes of insufficient thyroid replacement.”

Identifying thyroid replacement interference, absorption issues

“The study is of significant clinical interest as it addresses two common concerns: Is the patient really taking their medication appropriately or is there an absorption issue?” said Maria Brito, MD, co-director of The Thyroid Center at Mount Sinai at Union Square and assistant professor of medicine (endocrinology, diabetes, and bone disease) at the Icahn School of Medicine at Mount Sinai in New York City.

“Although the sample size of this trial was quite small, the investigators were able to confirm that most patients do absorb their thyroid medication adequately when taken appropriately, and so patients who may require parenteral (i.e., intravenous or intramuscular) forms of thyroid medication are rare,” Dr. Brito told EndocrineWeb.     

“To date, there has been no clinical test that we can use to answer these questions about levothyroxine absorption, and this study proposes a possible means of assessing rate of LT4 absorption,” she said. “However, I would like to see this study replicated with a larger cohort of patients to further validate the finding before it is likely to gain wider clinical adoption.”

The authors report no competing financial conflicts with regard to their involvement in conducting or discussing this study. 

Continue Reading:
American Thyroid Association Guideline: Treatment of Hypothyroidism Other Than Levothyroxine Monotherapy
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