Dichotomous Responses to Thyroid Hormone Treatment in a Patient with Primary Hypothyroidism and Thyroid Hormone Resistance

Introduction

R esistance to thyroid hormone (RTH) is a heritable syndrome characterized by reduced TH sensitivity most often due to point mutations in the β-isoform of the thyroid hormone receptor (TRβ). Based on a limited screening of 80,884 infants for elevated total thyroxine (T4) levels, it has been estimated that RTH affects at least 1 per 40,000 live births (1,2).

TRβ mutants interfere with the function of normal TRs, impairing negative feedback at the pituitary and hypothalamus and resulting in thyroid-stimulating hormone (TSH) and TH elevation. In most cases of RTH, tissue resistance to TH is compensated by increased TH levels. Thus, additional TH therapy is not usually necessary unless thyroid reserve has been diminished, most often as a consequence of prior ablative therapy (1,3,4).

Among previously reported cases of patients affected by Hashimoto's thyroiditis in association with RTH due to a documented TRβ mutation, the observed TSH elevation has been generally modest (5,6), with one report of a patient requiring TH replacement (7). We present a patient with RTH who developed significant hypothyroidism due to Hashimoto's thyroiditis.

Patient

A 66-year-old woman was referred to us because of abnormal thyroid function tests and progressive fatigue. She reported a history of goiter for which she underwent partial right thyroid lobectomy at age 17. She subsequently remained healthy through five uncomplicated pregnancies without any treatment and recalled that it was following the pregnancies, at age 39, that she was first noted to have abnormal thyroid function test results. Since then, she had been intermittently treated with levothyroxine while under the care of multiple consecutive endocrinologists who noted symptoms of both hypothyroidism and thyrotoxicosis along with laboratory studies demonstrating elevation of T4, triiodothyronine (T3), and TSH.

While taking Synthroid 50 mcg daily, TSH was 18.6 and both free T4 and free T3 were modestly elevated (Table 1). Because of palpitations and elevated TH levels, her Synthroid was discontinued by her primary care physician with prompt improvement in her palpitations. Four months following discontinuation of Synthroid, TSH was 31 μIU/mL, and T4 and T3 levels remained elevated. At that time, positive antithyroglobulin antibodies (63 IU/mL; normal range: 0–40) and negative thyroid peroxidase antibodies (19 IU/mL; normal range: 0–35) were noted.

Several months later, she developed progressive fatigue and muscular weakness. TSH was further elevated at 71 μIU/mL, and T4 and T3 levels had decreased to within the reference range. An I-123 thyroid scan with uptake was obtained, demonstrating a 24-hour uptake of 59.9% with heterogeneous distribution and asymmetric left-sided enlargement on scan, read as “compatible with Graves' disease or toxic nodular goiter.” Thyroid ultrasound demonstrated a diffusely heterogeneous and hypervascular thyroid gland with right lobe dimensions of 2.4 × 1.5 × 1.2 cm and left lobe dimensions of 4.7 × 2.3 × 2.6 cm, in keeping with the patient's history of right partial thyroid lobectomy. Multiple heterogeneous nodules were noted on the left.

TSH levels were confirmed after dilution, treatment with a heterophile antibody blocking reagent, and by a second immunoassay. Cytology from fine-needle aspiration (FNA) of thyroid nodules showed rare atypical follicular cells and Hurthle cells in a background of reactive follicular cells and lymphocytes. Also, macrophages, rare multinucleated giant cells, and colloid were present. Taken together, the patient's thyroglobulin antibody status, ultrasonographic gland appearance, and FNA cytology were consistent with a diagnosis of Hashimoto's thyroiditis. Pituitary MRI showed a subtle focal depression of the sellar floor without definite adenoma and was otherwise unremarkable. Sex hormone-binding globulin (SHBG) was low normal at 22 nmol/L (normal range: 17–95), and alpha subunit was 0.8 ng/mL (normal postmenopausal range: 0.9–3.3 ng/mL).

After the above studies, we were able to obtain additional detailed history from the patient's daughter, who was noted to have a high normal TSH (4.12 μIU/mL), elevated free T4 (2.3 ng/dL), and elevated free T3 (500 pg/dL) while on treatment with Levoxyl 150 mcg daily.

The patient agreed to TRβ gene testing (Quest Diagnostics, San Juan Capistrano, CA), which revealed that she was heterozygous positive for an RTH mutation resulting in replacement of arginine with histidine at amino acid position 438 in exon 10 of the TRβ gene (R438H). On the basis of her laboratory results, the patient's daughter was presumed to be likewise affected by RTH, a condition characterized by dominant inheritance, and referred for evaluation by a specialist.

Levothyroxine therapy has been reintroduced incrementally, and although our patient's fatigue and muscular weakness have responded to treatment, her adherence to this therapy has been limited by palpitations and intolerance to beta blockade.

Discussion

Clinically, RTH can be classified as either generalized resistance to TH, such that affected individuals are euthyroid or hypothyroid despite high circulating TH levels, or central resistance to TH, such that peripheral sensitivity to TH is relatively preserved and affected individuals manifest signs and symptoms of thyrotoxicosis (8 –10). The R438H mutation detected in our patient has been well described in association with generalized resistance to TH (11 –15).

At the time of the patient's referral to our clinic, 8 months after discontinuing Synthroid, her T3 and T4 had declined into the mid-normal range, TSH was markedly elevated, and she had symptoms of hypothyroidism with serology and cytology confirming Hashimoto's thyroiditis. Her 24-hour I-123 uptake was elevated at 59.9%, which is explainable on the basis of high TSH drive and in keeping with prior reports that the presence of Hashimoto's thyroiditis does not preclude the possibility of elevated radioiodine uptake (16,17).

There have been several reports of RTH in association with thyroid autoimmunity, including both Hashimoto's thyroiditis as well as Graves' disease (5 –7,18 –20). A recent study by Barkoff et al. found that individuals with RTH due to TRβ mutations were more likely than their unaffected first-degree relatives to have thyroid autoimmunity (21). The reason for this association remains unclear. Interestingly, the one previously reported patient with a documented TRβ mutation and significant hypothyroidism due to Hashimoto's was heterozygous for the same R438H mutation found in our patient (7).

This case demonstrates some of the challenges faced in the diagnosis and management of RTH. Like many affected by RTH, our patient originally presented many years ago with a goiter, palpitations, and high TH levels, all of which are common findings in primary hyperthyroidism. Many patients with RTH have been misdiagnosed and inappropriately treated with radioiodine ablation or surgery with resulting hypothyroidism. Our patient underwent surgery at a young age but had five subsequent healthy pregnancies without any infertility or pregnancy loss, indicating that her thyroid function remained intact without TH therapy during those years. The diagnosis of RTH was made nearly 50 years after her presentation with thyroid disease.

Regardless of the cause, treatment of significant hypothyroidism in a patient with RTH can be challenging. Our patient's adherence to levothyroxine therapy has been limited by palpitations, a frequent symptom even in well-compensated RTH. Cardioselective beta blockade may be employed as a possible option to limit palpitations, which occur in the setting of TH replacement. Unfortunately, our patient has proven intolerant to this approach because of the development of lightheadedness on each occasion that we have initiated beta blocker therapy.

Treatment goals for hypothyroidism in patients with RTH have not been well established, although normalization of TSH has been proposed as a convenient target (22). We are treating according to the patient's clinical response and believe that the TSH values and TH levels of family members affected by RTH, free of apparent thyroid autoimmunity, and living in regions of similar iodine sufficiency may also be instructive in establishing a reasonable TSH goal.