PMC8187942_01
Medical history, log TSH, and LT4 dose per bodyweight of the case patient. The dose of sertraline and ethynyl estradiol were 50 mg per day and 0.03 mg per day, respectively. The beginning dates of each medication were May 2015, September 2015, and September 2016. There was fluctuation of serum TSH level in spite of increasing LT4 dose over bodyweight. LT4, levothyroxine; Bwt, bodyweight.
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TSH was persistently high and amenorrhea occurred. The LT4 dose was gradually increased and finally reached 800 mug/day, but her TSH level failed to be normalized ( Figure 1 ). Her body weight change ( Figure 1 ) also could not explain the aberrantly high LT4 dose.
LT4 absorption test. The serum total T4 level increased and TSH level decreased in response to high dose of LT4 ingestion. Absorption rate of LT4 was 8.4%.
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T4 was not checked after loading of LT4 1,000 mug, re-loading of LT4 was done after 2 days. The test showed the absorption rate of 8.4% ( Figure 2 ), and true malabsorption status of LT4 without obvious organic problems was confirmed.
(A-K) Immunohistochemistry result of ileal LT4 transporters in distal ileum. The panels were taken at x 20 magnification, and inset represents x 40 magnification. OATP1C1 was expressed in both nucleus and brush border in control (A) and the patient (B). OATP2B1 and MCT10 were mainly expressed in brush border in control (C, E) and the patient (D, F), respectively. LAT1 was mainly expressed in brush border in control (G), whereas there was perinuclear staining in the patient (H). LAT2 was detected at both perinuclear area and brush border in control (I), but was stained at only perinuclear area in the patient (J). The expression of MCT8 was not able to check in the patient due to lack of remnant ileal tissue. It was mainly expressed in brush border in control (K).
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In terminal ileum, the staining patterns of OATP1C1, OATP2B1, and MCT10 were similar between control and the patient ( Figures 3A-F ). LAT1 and LAT2 were stained at brush border in controls, but both were not stained at brush border in the case patient - the staining was limited to nucleus or perinuclear area ( Figures 3G-J ). MCT8 was mainly expressed at brush border in controls ( Figures 3K ).
(A-L) Immunohistochemistry result of ileal LT4 transporters in ascending colon. The panels were taken at x 20 magnification, and inset represents x 40 magnification. OATP1C1 was expressed in both nucleus and brush border in control (A) and the patient (B). OATP2B1 was expressed in brush border in control (C) and the patient (D). MCT10 staining was weak and limited to brush border in control (E) and the patient (F). LAT1 was mainly stained at brush border in control (G), but was mainly stained at nucleus in the patient (H). While LAT2 was stained at both nucleus and brush border in control (I), it was stained at only perinuclear area in the patient (J). MCT8 was expressed in brush border in control (K), but was expressed in both nucleus and brush border in the patient (L).
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The staining patterns of OATP1C1, OATP2B1, and MCT10 were similar in both groups, as was terminal ileum ( Figures 4A-F ). In the patient, the membranous expression of LAT1 and LAT2 was decreased as in terminal ileum ( Figures 4G-J ). MCT8 was expressed in brush border in control, which was similar to ileum, but was expressed in both nucleus and brush border in the patient ( Figures 4K-L ).
Expression of SLCO1C1 (OATP1C1), SLCO2B1 (OATP2B1), SLC16A10 (MCT10), SLC7A5 (LAT1), SLC7A8 (LAT2), and SLC16A2 (MCT8) in gastrointestinal tract. Violin plots were used to express the TPM data of transporters in each tissue. The colors indicate the different tissues. TPM, transcripts per million.
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In order to check whether the expression of thyroid hormone transporters in ileum and colon is parallel, the expression pattern of LT4 transporters in large-scale healthy population was confirmed via Genotype-Tissue Expression (GTEx) data ( Figure 5 ).