Consumptive Hypothyroidism in GIST Associated With Increased D3 Expression
In a report in The New England Journal of Medicine, Maynard et al discuss identification of consumptive hypothyroidism due to overexpression of thyroid hormone–inactivating enzyme type 3 iodothyronine deiodinase (D3) in a patient with gastrointestinal stromal tumor (GIST) and subsequent investigations showing that high D3 activity is common in GIST and may be associated with hypothyroidism. Tyrosine kinase inhibitor treatment in GIST is associated with hypothyroidism and may increase risk of the condition by increasing tumor D3 expression. Affected patients warrant increased monitoring and may require very high levels of thyroid hormone supplementation.
Identification of Consumptive Hypothyroidism
In the index patient described by the authors, diagnosis of a large abdominal GIST and treatment with surgery was followed at 2 years by development of metastatic disease; this prompted initiation of imatinib (Gleevec) treatment, which was discontinued after 10 months due to disease progression, and then sorafenib (Nexavar) treatment, which was discontinued after 5 months due to progression, and then sunitinib (Sutent) treatment started at 6 months after discontinuing sorafenib.
Testing before the start of sunitinib treatment showed hypothyroidism with an elevated thyrotropin level and low normal total thyroxine and triiodothyronine uptake levels. Despite levothyroxine doses as high as 300 μg, thyrotropin levels remained elevated, with subnormal levels of thyroxine and triiodothyronine; during hypothyroxinemia, the level of serum reverse triiodothyronine was markedly elevated. Sunitinib was continued until the patient’s death from tumor progression 23 months later.
D3 Activity Common in GIST
As noted by the authors, the massive tumor burden and supernormal requirement for exogenous thyroid hormone in this patient raised the possibility of consumptive hypothyroidism. Immunostaining of biopsy samples from before the start of sunitinib showed strong D3 expression in GIST cells and assessment of frozen GIST tissue from the time of first surgery also showed dramatic D3 activity.
Genotyping showed a somatic PDGFRA exon 18 mutation in the tumor sample. Such mutations are found in approximately 10% of patients with sporadic GIST. However, tumor samples from three other GIST patients with KIT exon 11 mutations (found in 60%–80%) or a KIT exon 9 mutation (found in 10%–15%) also showed strong D3 activity.
Subsequent assessment of 28 surgical GIST specimens showed D3 activity in 23 (82%), with activity across all genetic subtypes of GIST and in samples from 11 patients who were not receiving tyrosine kinase inhibitor therapy at the time of surgery. Hypothyroidism was present in 4 of 15 patients with available data, with all tumors exhibiting D3 activity, including two in patients with KIT-mutated GIST who required very high doses of levothyroxine.
Tyrosine Kinase Inhibitors Increase D3 Expression
Studies in the imatinib-sensitive GIST-T1 cell line showed that endogenous D3 activity in the basal state was similar to that observed in tumor tissues, with exposure to imatinib or sunitinib at therapeutic doses increasing D3-specific activity by as much as 1.8-fold and messenger RNA by as much as 4.8-fold.
Comparison of the effects of blockade of D3 activity of GIST-T1 cells (with iopanoic acid) and the effects of imatinib exposure showed that imatinib, as expected, significantly decreased GIST-T1 cell proliferation and viability and induced apoptosis, whereas no significant effect on these measurements was observed with D3 inhibition by iopanoic acid either alone or in combination with imatinib.
The authors noted, “From a clinical standpoint, a therapy-induced increase in tumoral D3 expression (as we observed in cultured GIST-T1 cells exposed to tyrosine kinase inhibitors) could contribute to the increased incidence of hypothyroidism associated with these antineoplastic agents. Further studies of D3 expression in tumor-biopsy specimens obtained from patients both before and during therapy with tyrosine kinase inhibitors may be warranted to test this hypothesis.”
They concluded, “Monthly measurement of serum thyrotropin in all patients with a large GIST burden and symptoms of hypothyroidism, even if tyrosine kinase inhibitors have never been used, could avoid the complications of occult hypothyroidism and the risk of incorrectly attributing hypothyroid symptoms to the cancer or chemotherapy.”
Stephen A. Huang, MD, of Boston Children’s Hospital, is the corresponding author for The New England Journal of Medicine study.
The study was supported by the Murray Family and grants from the National Institutes of Health, William F. Milton Foundation Award, and Harvard Clinical and Translational Science Center. For full disclosures of the study authors, visit www.nejm.org.
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