Resistance to Thyroid Hormone in a Patient with Coexisting Graves' Disease

Introduction

G raves' disease is an autoimmune disorder in which hyperthyroidism results from excessive stimulation of the thyroid gland by thyroid-stimulating immunoglobulins (TSIs). TSIs bind to and activate thyrotropin receptors causing growth of the thyroid gland, as well as increased synthesis of thyroid hormone by thyroid follicles.

Thyroid hormones act on the carboxy-terminal domain of thyroid receptors (TRs) that belong to the family of steroid nuclear receptors. TRs bind to thyroid response elements that are located in the promoter regions of target genes. The two subtypes of TRs, TRα and TRβ, are encoded by genes on chromosomes 17 and 13, respectively (1).

First described by Refetoff et al. in 1967, resistance to thyroid hormone (RTH) is a disorder in which there is reduced end-organ sensitivity to thyroid hormones (2). This is usually due to mutations in the TRβ, but may also occur due to thyroid hormone cell membrane transporters or genes controlling the intracellular metabolism of thyroid hormone (1). This results in the reduced clinical and biochemical manifestations of thyroid hormone action relative to levels of the circulating hormones. Three forms of RTH have been described, including pituitary resistance (PRTH), generalized resistance (GRTH), and peripheral RTH (PerRTH). The classification of PRTH and GRTH is somewhat arbitrary, as these two disorders may fall along a clinical spectrum of disease, and a wide overlap of signs and symptoms exhibited by individuals with GRTH or PRTH is reported (3). Also, different clinical features have been observed in affected individuals in the same kindred having the same thyroid hormone beta-receptor mutation. Moreover, identical mutations have been identified in unrelated kindreds classified as GRTH or PRTH. This supports the view that GRTH and PRTH are variable manifestations of a single genetic entity. The pathophysiology of PerRTH is less well understood.

Because patients with RTH may present with a goiter, palpitations, and elevated thyroid hormones, they are frequently misdiagnosed as having Graves' disease (1). This often leads to inappropriate medical investigations and treatment (1,4).

Although Graves' disease is a commonly encountered thyroid disorder with an estimated prevalence of 0.8%, RTH is a rare disease with a prevalence of only 1 in 40,000 (5,6). In a previous report, one patient with Graves' disease was found to have concurrent pituitary RTH (7). This was published before gene sequencing could be used to confirm diagnosis of RTH. We present a patient with Graves' disease and concurrent RTH that was confirmed by gene sequencing, showing a mutation in the thyroid hormone receptor β gene.

Patient Findings

A 53-year-old Caucasian male was found to have a goiter on routine evaluation by his primary care physician. The patient reported an increased appetite, as well as weight loss and anxiety for several preceding months. Thyroid function tests (TFTs) showed a low thyroid stimulating hormone (TSH) and elevated levels of T3, T4, and free thyroxine index (Table 1, Column 1). Repeat testing confirmed these results. The patient was found to have an elevated TSI (143%; reference range <130%), and an Iodine-123 (I-123) uptake was found to be 40% (reference range 5–15%) at 6 hours with homogenous activity throughout both lobes of the thyroid gland which appeared slightly prominent. He was also found to have antimicrosomal antibodies 101.5 U/mL (reference range <1) and antithyroglobulin antibodies 1.6 U/mL (reference range <1).

Graves' disease was diagnosed in the patient based on his symptoms of hyperthyroidism, depressed TSH, high T3 and T4 levels, and elevated TSI. He underwent ablation of the thyroid gland with 10 mCu of Iodine-131 and subsequently developed hypothyroidism in the following months. Table 1, Column 2 shows his TFTs 6 months postablation. The patient was initially started on levothyroxine (LT4) 25 μg daily, which was increased over the next few months. He required titration to high doses of LT4 to achieve clinical euthyroidism and normalization of TSH levels. Table 2, Rows 1–3 show his TFTs on 250, 300, and 325 μcg of LT4, respectively. His increased levels of T4 and T3 despite the normal TSH levels at the higher doses raised the question of RTH.

The patient underwent genetic testing and was found to have a thyroid hormone receptor β gene mutation G347W. A guanine to thymine base substitution at nucleotide position 1339 which altered codon-347 from glycine (GGG) to tryptophan (TGG) was identified. Genetic testing of the patient's mother and his son showed that neither of them carried this mutation. The patient's son also had normal results on routine TFTs. The patient's father was deceased and could not be tested.

Currently, the patient has been clinically euthyroid on a stable dose of 325 μg of daily levothyroxine with a TSH of 1.29μIU/mL.

Discussion

RTH is usually inherited in an autosomal dominant manner (8). Thus, the lack of the mutation in the patient's mother indicates that either he inherited the gene from his father or this represents a de novo mutation, which is found in 22.5% of patients with RTH (1). Affected individuals are heterozygous for mutations and this may explain why his son did not carry the mutation. In all, 122 different point or frameshift mutations clustered in three regions in the TRβ gene have been found to be associated with RTH (9). One region encompasses codons 310–347 (10). Genetic testing of our patient revealed that he possessed the TRβ gene mutation G347W as described.

In addition to TSI, the patient also had elevated antimicrosomal antibodies. A number of reports exist in which RTH has been associated with thyroid autoimmunity, mainly Hashimoto's thyroiditis (11,12,13). One report suggests that patients with RTH with high titers of antithyroid antibodies are more likely to require thyroid hormone supplementation (13). However, considering the high prevalence of thyroid autoimmunity, particularly Hashimoto's thyroiditis, it is expected that some rare patients will have autoimmune hypothyroidism coexisting with RTH.

Graves' disease is one of the most prevalent autoimmune diseases with an estimated prevalence of 0.8% in the United States (6,13). Considering a prevalence of 1 in 40,000 for RTH, it might be expected that 1 in 5,000,000 people in the United States will have coexisting Graves' disease and RTH. One previous report exists describing a patient with pituitary RTH and concurrent Graves' disease (7). However, at that time of the publication by Pillay et al., genetic testing for TRβ gene mutations was not available, and thus the diagnosis of RTH was confirmed only by thyroid releasing hormone (TRH) stimulation testing.

Graves' disease is the most common cause of hyperthyroidism and is relatively straightforward to diagnose. Considering the relative prevalence of Graves' disease, and the rarity of RTH, patients with RTH are often misdiagnosed as having Graves' disease (1,4). This is due to the fact that patients with either disorder may have a goiter, tachycardia or palpitations, high levels of total and free thyroid hormone levels, and increased I-123 uptake on nuclear scan of the thyroid gland. This misdiagnosis has been reported to result in various inappropriate treatments (4,15,16). Thus, it is important to differentiate between these two disorders.

Evidence for the existence of Graves' disease in our patient is given by the presence of signs and symptoms of hyperthyroidism along with elevated thyroid TSIs and high levels of T3 and T4 and a suppressed TSH This combination of findings would not be present in isolated RTH.

Following radioactive iodine ablation of the thyroid gland, the patient's levothyroxine dose was progressively increased over the next few years as he continued to exhibit both signs of hypothyroidism as well as an elevated TSH level. Table 2, Row 1 shows that while taking 250 μg of LT4, he continued to have an elevated TSH, despite high levels of T3 and T4. At this point, medication noncompliance, impaired absorption of thyroid hormone supplementation, and increased metabolism of thyroid hormone can be excluded because the patient had high levels of T3 and T4. This raised the possibility of RTH, which was later demonstrated on genetic testing.

The number of years that elapsed before the diagnosis of RTH was established in our patient shows how challenging this diagnosis can be to render, especially if it occurs in the setting of concurrent Graves' disease. In his initial TFTs (Table 1, Column 1), his TSH is only slightly suppressed in the setting of notably high total T3 levels and free thyroxine index. This is perhaps the first clue that the patient had RTH in addition to Graves' disease. As patients with RTH vary in clinical spectrum, the level of thyroid hormones required to suppress their TSH cannot be precisely defined. Patients with RTH may have thyroid hormone supplementation at doses two to three times larger than usual replacement doses without producing suppression of TSH or clinical hyperthyroidism. However, very large doses of levothyroxine (330–900 μg daily) or liothyronine (100–500 μg daily) can partially or completely suppress pituitary TSH response to TRH and I-131 uptake by the thyroid gland (4). The clinical hyperthyroidism experienced by our patient due to Graves' disease was likely abated by his concurrent RTH, resulting in only minimal suppression of TSH.

Diagnosis of RTH is suggested by normal to elevated TSH along with elevated serum free T3 and T4 levels in the absence of clinical features of hyperthyroidism. A suspicion of inappropriate TSH secretion should be raised if the TSH and free T3 and T4 levels are all elevated in the setting of clinical hyperthyroidism. If this occurs a TSH α-subunit level and pituitary MRI or pituitary scintigraphy with radiolabeled octreotide (octreoscan) can be ordered to rule out a TSH-secreting pituitary adenoma, most of which present as macroadenomas (17). Also, in RTH, patients have a normal or supranormal increase in TSH following TRH administration, whereas in TSH-secreting adenomas, TRH stimulation fails to cause more than a twofold rise in TSH secretion (17).

Features that both Graves' disease and RTH share include elevated free thyroid hormone levels, increased iodine uptake on thyroid nuclear scan, and the presence of a goiter and palpitations or tachycardia. Stigmata specific to Graves' disease such as exopthalmous and pretibial myxedema should not be present in a patient with isolated RTH, nor should one find elevated levels of TSI. Because RTH is usually inherited in an autosomal dominant manner, a family history may be helpful. Considering that patients with RTH are often mistaken as having Graves' disease, the family history may reveal that a number of family members have undergone inappropriate treatment after a misdiagnosis of Graves' disease or hyperthyroidism. Also, because the thyroid hormone β receptor has been sequenced and numerous mutations resulting in the RTH phenotype are known, genetic testing can aid in distinguishing Graves' disease from RTH. A TRβ mutation can be found in 90% of patients with RTH (17). First-degree family members of patients harboring a known mutation should be genetically screened as well, to prevent potential misdiagnosis and inappropriate treatment.

Because patients with RTH are often misdiagnosed as having Graves' disease, many of them will undergo radioactive iodine ablation of the thyroid gland or thyroidectomy which will necessitate subsequent thyroid hormone supplementation. Patients who require supplementation at much higher doses than calculated weight-based estimates to maintain clinical euthyroidism after ablation or those who continue to have elevated TSH levels despite high doses of supplementation should undergo TRH stimulation and genetic testing for RTH.

Clearly, our patient's clinical investigations and findings are consistent with a diagnosis of Graves' disease with coexisting RTH. Although there was evidence of RTH even on the patient's initial TFTs, this diagnosis did not become apparent until after radioactive iodine ablation of the thyroid gland when the confounding effects of Graves' disease were eliminated. Our patient illustrates some of the difficulties encountered in the diagnosis of thyroid dysfunction, particularly for the combination of rare RTH with coexisting Graves' disease. It also highlights the importance of critically evaluating TFTs in association with clinical findings for clues regarding concurrent disorders.