Recurrent Graves’ hyperthyroidism after prolonged radioiodine-induced hypothyroidism

Abstract

Background:

Radioactive iodine (RAI) is the most cost effective therapy for Graves’ disease (GD). Patients with GD who have become hypothyroid after therapeutic RAI, rarely develop recurrence of disease. Herein we describe a case of recurrence of thyrotoxicosis after 2 years of hypothyroidism.

Methods:

We present the clinical features, laboratory findings, imaging and management of an unusual case of recurrent hyperthyroidism.

Results:

A 48-year-old male presented to the emergency room with a 2-day history of palpitation, chest discomfort and 30 pounds of weight loss. Examination was remarkable for rapid and irregular pulse, diffuse thyromegaly and brisk deep tendon reflexes but no eye changes or tremors. Laboratory tests showed thyroid-stimulating hormone (TSH) of <0.004 (0.3–5.6 mIU/ml), free thyroxine (FT4) 4.96 (0.9–1.8 ng/dl), free triiodothyronine (FT3) >20 (1.8–4.7 pg/ml), total thyroxine >800 (80–200 ng/dl). Electrocardiogram showed atrial fibrillation with rapid ventricular response. RAI uptake and scan showed a homogenous gland with 54% uptake in 6 h and 45% in 24 h. He was treated with propranolol and propylthiouracil with some clinical improvement. He subsequently underwent RAI therapy and developed hypothyroidism after 8 weeks. Hypothyroidism was treated with levothyroxine. At 2 years after RAI ablation, he again developed symptoms of hyperthyroidism and had suppressed TSH. The levothyroxine dose was stopped, 3 weeks after discontinuing levothyroxine, he remained hyperthyroid with TSH of 0.008 and FT4 of 1.62 and FT3 of 4.8. RAI uptake demonstrated 17% uptake at 24 h.

Conclusion:

Recurrent hyperthyroidism in GD is uncommon after development of post-ablative hypothyroidism. Our case illustrates the need for continued surveillance.

Introduction

Graves’ disease (GD) is the most common cause of hyperthyroidism, which is responsible for approximately 50–60% of the cases.¹

Iodine 131 (I-131) ablation is the preferred method of treatment in the United States (US). The use of radioactive iodine (RAI) therapy is on the rise as it is relatively inexpensive, well tolerated, easy to administer and highly effective with a cure rate approaching 100% after one or more treatments.¹

RAI therapy is administered as a single dose or multiple doses over months to achieve remission. The endpoint of successful treatment is sustained hypothyroidism or occasionally euthyroidism. Once hypothyroidism has been achieved, it is usually irreversible with the patient requiring lifelong thyroid replacement. Recurrence of hyperthyroidism after RAI therapy may be due to inadequate dosing or early Marine Lenhart syndrome. Herein we report a rare case of recurrent Graves’ hyperthyroidism occurring after 2 years of successful radioiodine treatment.

Case report

A 48-year-old White male presented to the emergency room with a 2-day history of palpitation, chest discomfort and 30 pounds of weight loss, despite an increased appetite. He exhibited significant emotional lability. The patient had no significant past medical history but he had a family history of thyroid disease. He was a truck driver by profession who smoked cigarettes and used marijuana in the past. Physical examination was remarkable for an irregular pulse rate of 150/min, diffuse thyromegaly and brisk deep tendon reflexes. He had no eye findings or tremors. Ancillary investigations showed suppressed thyroid-stimulating hormone (TSH) <0.004 (0.3–5.6 mIU/ml), free thyroxine (T4) of 4.96 (0.9–1.8 ng/dl), free total thyroxine (T3) > 20 (1.8–4.7 pg/ml) and T3 > 800 (80–200 ng/dl). Electrocardiogram showed atrial fibrillation with a rapid ventricular response. Thyroid scintigraphy revealed a homogenous gland with 54% uptake at 6 h and 45% at 24 h. The patient was treated with propranolol 120 mg and propylthiouracil 200 mg every 6 h initially and subsequently with 20.5 mCi of RAI. The antithyroid drug was discontinued a week prior to RAI ablation. At 8 weeks after ablation, the patient had clinical and laboratory evidence of hypothyroidism (free T4 0.44 (0.9–1.8 ng/dl), TSH 18.25 (0.3–5.6 mIU/ml) as shown in point B in Figures 1 and 2. Treatment was initiated with oral levothyroxine 125 mcg daily. Atrial fibrillation resolved, with a regular heart rate of 70–80 beats per minutes. At 16 months after administration of RAI, TSH was noted to be low but free T4 remained within normal limits; however, at 20 months, TSH was suppressed and free T4 was elevated and symptoms of hyperthyroidism has recurred including palpitation, sweating, irritability and fatigue (point C in Figures 1 and 2). Thyroid function tests revealed undetectable TSH of <0.008 (0.3–5.6 mIU/ml), and elevated free T4 of 2.01 (0.9–1.8 ng/dl), levothyroxine was discontinued for 3 months but the patient remained hyperthyroid with TSH of 0.008 and free thyroxine (FT4) of 1.62 and free triiodothyronine of 4.8. Serology revealed thyroid-stimulating antibody 455 (0–139%) and thyroid peroxidase antibody 321 (0–4 IU/ml). A thyroid ultrasound was obtained to exclude thyroid nodules: The right thyroid lobe measured 1.8 × 3.7 × 1.9 cm and the left lobe 1.3 × 3.1 × 2.0 cm; no discrete nodules were identified but there was coarsening of the fibrous tissue and echotexture consistent with previous radioiodine therapy. The patient had repeat RAI uptake and scans which revealed uptake of 17% in 24 h. At 6 years after the initial RAI ablation he was treated again with 22.2 mCi of I 131 and subsequently developed post-ablative hypothyroidism. He has been taking levothyroxine 150 mcg orally daily and his last thyroid function tests showed TSH of 7.550 (0.3–5.6 mIU/ml) and FT4 1.05 (0.9–1.8 ng/dl).

Figure 1.

Free T4 levels over time.

T4, thyroxine.

Figure 2.

TSH over time.

TSH, thyroid-stimulating hormone.

Discussion

GD affects about 0.5% of the population, predominantly patients aged 40–60 years with a female to male ratio of 5:1 to 10:1.² Thyroid antibodies activate the TSH receptor to increase thyroid hormone production.

There are three major modalities for the treatment of GD including thionamides, RAI therapy and surgery. RAI and surgery are considered definitive treatment options since they can destroy or remove all hyperfunctioning thyroid tissue. Antithyroid medications can be used for a defined period of time (12–18 months) in the hope of remission. However, these medications are generally not long-term treatment options due to their side effects and inability to produce sustained remission after 18 months of treatment. Therefore, most patients suffering from hyperthyroidism may ultimately require radioiodine treatment or surgery. Surgery is less commonly used and is usually reserved for patients with large goiter, intolerance to antithyroid drugs and difficulties in administering radioiodine. Radioiodine is a more popular therapy in the US when compared with Europe or Japan where the preference is for antithyroid drug therapy.

RAI was first developed in 1934, and its clinical use began in1941 when Hertz and Roberts first treated patients with hyperthyroidism at the Massachusetts General Hospital, USA.^{3, 4} The usual therapeutic dose of RAI ranges from 5–15 mCi, determined either by using various formulae that take into account the estimated thyroid weight and radioiodine uptake or by using fixed dosages of iodine I 131. A fixed dose of 7 mCi has been advocated by some researchers as the first empirical dose in the treatment of hyperthyroidism.⁵ In general, higher dosages are required for patients who have large goiter, have low radioiodine uptake, or who have been pretreated with antithyroid drugs. In theory, the therapeutic goal of I-131 administration is to induce euthyroidism so that GD cannot recur. However, the incidence of hypothyroidism is significant during the first year or two after treatment with RAI, regardless of how the dose is calculated, and hypothyroidism usually occurs quite rapidly after RAI therapy. Hypothyroidism occurs in approximately 80% of patients receiving high-dose therapy (160 microCi/g) and 10% of patients receiving low-dose therapy (80 microCi/g).⁵ Once hypothyroidism has been achieved, it is usually irreversible with the patient requiring lifelong thyroid replacement. Early recurrences are reported in 20–54% of cases within 3–6 months, which can be due to inadequate RAI treatment or early Marine Lenhart syndrome.⁶ True recurrence is relapse after an extended period of time following attainment of hypothyroidism. Our patient developed recurrent thyrotoxicosis after he had been hypothyroid for about 16 months; TSH was noted to be low but free T4 remained normal until 20 months when he developed symptoms of hyperthyroidism associated with elevated free T4 and suppressed TSH. Although the occurrence of hypothyroidism after 2 months of RAI therapy would raise suspicion of stunning, it is noteworthy that stunning typically resolves in 2–4 weeks.^{7, 8} Furthermore, the incidence of stunning is reported to be less than 2% in patients treated with more than 12.8 mCi of I-131⁹; given that our patient received 20.5 mCi during his initial treatment, the likelihood of stunning would be very small. Marine Lenhart syndrome results from an autonomous thyroid nodule within a diffuse goiter. However, this was excluded in our patient as we demonstrated homogenous RAI uptake. Conventional doses of radioiodine may be insufficient for Marine Lenhart syndrome. Other putative mechanism may relate to the autoimmune nature of GD; in subjects with high antibody titers and severe hyperthyroidism, I-131 may be secreted very rapidly from the thyroid gland. Thus, resulting in failure of complete ablation and possible recurrence of disease.¹⁰

Conclusion

Hyperthyroidism rarely recurs in GD after successful treatment with a relatively large dose of RAI and after prolonged period of post-ablative hypothyroidism. Our case illustrates the need for continued surveillance after successful treatment with RAI.