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Exp Clin Endocrinol Diabetes 2023; 131(12): 629-630
DOI: 10.1055/a-2210-1109
Editorial

Levothyroxine Absorption Test – An Underused Tool

Karsten Müssig 
1   Department of Internal Medicine, Gastroenterology and Diabetology, Niels Stensen Hospitals, Franziskus Hospital Harderberg, Georgsmarienhütte, Germany
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Over the past few months, a 34-year-old and a 24-year-old female patient presented to our department with persistent clinical and biochemical signs of hypothyroidism after thyroidectomy for Graves’ disease despite high doses of levothyroxine (LT4) replacement therapy of up to 500 μg daily. Both patients assured that they were taking their medications regularly and correctly. Furthermore, they denied gastrointestinal symptoms, such as voluminous diarrhoea, steatorrhoea, meteorism, flatulence and food intolerances. Free thyroxine (FT4) and free triiodothyronine (FT3) levels were decreased, whereas thyroid-stimulating hormone (TSH) levels were markedly increased. A gastrointestinal workup including oesophagogastroduodenoscopy was unremarkable without any signs of celiac disease. In both cases, a levothyroxine absorption test (LT4AT) with hourly measurement of FT4 and total thyroxine (TT4) over four hours after the administration of 600 μg LT4 liquid solution revealed normal LT4 absorption. Supervised once weekly oral LT4 was advised.

Hypothyroidism is a common endocrine disorder that can usually be treated well with adequate thyroid hormone replacement therapy. In a few patients, clinical and biochemical signs of hypothyroidism persist despite therapy with high doses of LT4. While thyroid hormone resistance is present in only very few cases, frequent causes are poor medication adherence or gastrointestinal malabsorption. The LT4AT is a safe and cost-effective measure for differentiating between true malabsorption or pseudomalabsorption resulting from poor medication adherence [1]. Various published and non-published protocols are used with differences in test dose, formulation, test duration, frequency of blood sampling, analyte (TT4 or FT4), metric (absolute or relative peak or increment, or area under the curve) and criteria for normal absorption [2]. The available protocols agree that the patient remains fasting overnight and should not consume food, beverages, or medications in the morning of the test. Before starting the test, a venous line should be inserted and the first blood sample taken for the determination of FT4 and/or TT4. Subsequently, a supraphysiological LT4 dose, usually ranging between 600 and 1000 μg, is administered orally. Further blood samples are taken every hour for the next four to six hours after LT4 administration. The patient should be monitored throughout the test.

Assuming a molecular weight of LT4 of 776.87 g/mol, a volume of distribution of 10–12 l and a maximum absorption of orally administered LT4 from the upper small intestine of 80% [3], the theoretical maximum increase in TT4 concentration would range from (772 nmol [600 μg]/12 l*0.8)=51.5 nmol/l to (772 nmol [600 μg]/10 l*0.8)=61.8 nmol/l after administration of 600 μg LT4 in a normal weight person. In a previous study, the LT4 dosing was chosen depending on the patient’s age and body mass index (BMI): age 18–65 years, BMI<40 kg/m2: 1000 μg; age 18–65 years, BMI≥40 kg/m2: 1500 μg and age 65 years and older: 600 μg [4]. LT4 absorption was calculated using the following formula, with normal absorption being≥60%:% Absorbed=[[Increment TT4 (µg/dl)*10/total administered LT4 (µg)]]*Vd (l)*100, with increment TT4=peak [TT4] – baseline [TT4] and Vd (volume of distribution)=0.442*BMI. The testing protocol of another study included the oral administration of 1000 μg of LT4 with subsequent serial measurements of FT4 and TT4 at times 0, 30, 60, 90, 120, 180, 240, 300, and 360 minutes. Since FT4 and TT4 levels associated highly, even in patients with severe hypothyroidism, FT4 may be used interchangeably with TT4 during LT4AT [5]. In line with this assumption, a recent study revealed that a LT4AT with hourly measurements of FT4 over 6 hours after administration of 1000 μg LT4 is a reliable test to differentiate between true malabsorption and pseudomalabsorption, with more than 60–80% absorption indicating normal absorption [6]. The protocol of another study included administration of LT4 (10 μg/kg body weight or maximum 600 μg) with subsequent measurements of FT4 levels at hourly intervals for 5 hours. The cut-off of FT4 increment at 3 hours after LT4 administration above 0.40 ng/dl (5.14 pmol/l) had a sensitivity of 97% and specificity of 80% to exclude true malabsorption [7]. In a further study, LT4 dosis depended on body weight with 15 μg/kg bodyweight (except for one patient who received 12 μg/kg). Hourly samples for TT4 were taken for 5 hours after LT4 administration. Absorption of>60% was defined as normal. In addition to its capacity to discriminate between true malabsorption and pseudomalabsorption, LTAT facilitated reinforcement of compliance and thereby LT4 dose reduction [8].

Even though different protocols are available, the LT4AT is a safe and non-invasive procedure that allows differentiation between true malabsorption and pseudomalabsorption, thus sparing the patient concerned unnecessary diagnostics.



Publication History

Article published online:
06 December 2023

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