Transition from hypothyroidism to Graves’ disease, development of thyroid eye disease, progression to optic neuropathy after inpatient pulse therapy, and long-term administration of outpatient pulse therapy: a case report with review of literature

Abstract

A 55-year-old woman transitioned from hypothyroidism to Graves’ disease (GD) and then developed thyroid eye disease (TED) with proptosis and diplopia. After three cycles of daily methylprednisolone pulse therapy, her condition progressed to dysthyroid optic neuropathy with decreased visual acuity in both eyes. Her clinical activity score (CAS) was 7 points. Orbital magnetic resonance imaging (MRI) showed that the enlarged extraocular muscles were compressing the optic nerve in the area of the cones. Although her visual acuity recovered during two further cycles of daily pulse therapy, disease activity persisted for 4 years. TED exacerbated five times. Each time, the patient received weekly pulse therapy with no adverse reactions until her ophthalmopathy was relieved. The total cumulative dose of methylprednisolone was 59.5 g. Thyroid-stimulating antibody (TSAb) was positive from the time of hypothyroidism onset and became strongly positive with the onset of GD and the progress of TED. In addition, MRI was useful for the evaluation of the pathophysiology of ophthalmopathy. This case report suggests that careful monitoring by both endocrinologists and ophthalmologists using CAS, ophthalmological assessments, TSAb measurement, and orbital MRI are useful for making treatment decisions for TED.

Introduction

Dysthyroid optic neuropathy (DON), the most severe and sight-threatening form of thyroid eye disease (TED), is found in 0.9% to 8.0% of patients with TED [1-3]. DON is caused by compression of the optic nerve by swollen extraocular muscles, resulting in visual impairment. Therefore, urgent treatment at a specialized hospital is required. Intravenous infusion of methylprednisolone (MP) pulse therapy is the first-line treatment [4-7]. If there is no sign of improvement within 2 weeks of starting pulse therapy, emergency ophthalmic decompression surgery is indicated. If there is a positive trend in vision restoration, treatments such as additional pulse therapy and/or orbital irradiation therapy should be continued; however, the total dose of MP should be limited to <8 g because of the potential for severe liver toxicity [4-7]. Notably, the effect of MP is often insufficient, and the disease activity of TED persists for a long period. Thus, there is an unmet need to address the treatment gap for these patients. We carefully treat such patients with outpatient pulse therapy.

We herein report a case involving the transition from hypothyroidism to Graves’ disease (GD) and then to DON, which was difficult to treat.

Case Report

A 55-year-old woman was diagnosed with hypothyroidism due to chronic thyroiditis at the time of hospitalization for cerebral infarction in December X (Figs. 1, 2). Her blood test results were as follows: serum free thyroxine (FT4), 0.56 ng/dL (reference range, 0.83–1.77 ng/dL); thyroid-stimulating hormone (TSH), 59.04 mIU/L (0.61–4.23 mIU/L); TSH receptor antibody (TRAb; first-generation assay), 76.9% (<15%); thyroid-stimulating antibody (TSAb), 475% (<120%); anti-thyroglobulin antibody (TgAb), 257 IU/mL (<28 IU/mL); and anti-thyroid peroxidase antibody (TPOAb), 9 IU/mL (<16 IU/mL). Therefore, she was treated with levothyroxine. However, she transitioned to hyperthyroidism and was diagnosed with GD in November X + 1 (free triiodothyronine [FT3], 9.36 pg/mL [2.51–4.16 pg/mL]; FT4, 2.31 ng/dL; TSH, <0.01 mIU/L; TRAb (third-generation assay), >40 IU/L [<2.0 IU/L]). She was treated with 15 mg of methimazole. In November X + 2, she became aware of proptosis in her right eye and was diagnosed with TED in December X + 2. In March X + 3, she was hospitalized and underwent three cycles of 1 g daily pulse therapy (intravenous infusion of 1 g MP for 3 consecutive days/week) with oral administration of prednisolone (PSL) 30 mg/day. However, there was little improvement. During the PSL tapering therapy, the diplopia and exophthalmos in her left eye worsened on May X + 3 (Fig. 1). The orbital MRI showed enlargement of the bilateral rectus muscles (Fig. 2). Her corrected visual acuity was 1.2 in both eyes in early June X + 3, 2 weeks before referral to our hospital.

Fig. 1  Patient’s clinical course

MRI: magnetic resonance imaging, Tbc: tuberculosis, LT4: levothyroxine, 1 g Pulse: 1 g daily pulse therapy, 0.5 g Weekly Pulse: 0.5 g weekly pulse therapy, 0.5 g Pulse (every 2 wks): 0.5 g pulse therapy every two weeks, PSL: prednisolone, TA: local injection of triamcinolone acetonide; TRAb 1^st: thyroid-stimulating hormone receptor antibody (first-generation assay), TRAb 3^rd: thyroid-stimulating hormone receptor antibody (third-generation assay), TSAb: thyroid-stimulating antibody, CAS: clinical activity score

Fig. 2  Brain and orbital magnetic resonance imaging (MRI)

(A) Brain MRI (T1-weighted image in horizontal sections) showed left acute cerebral infarction (upper, arrow). There was no proptosis (lower).

(B–G) Orbital MRI (upper, T1-weighted coronal section image; middle, short tau inversion recovery (STIR) coronal section image; lower, T1-weighted horizontal section image). Proptosis and the signal intensity ratio of the enlarged eye muscles were assessed as previously reported [5, 8]. (B) The right inferior rectus muscle and medial rectus muscle were enlarged, resulting in proptosis on December X + 2. (C) MRI showed enlargement of all extraocular muscles in both eyes, and TED progressed despite three cycles of daily pulse therapy. (D) The patient had developed visual loss in both eyes at her first visit to our hospital. MRI showed enlargement of all extraocular muscles in both eyes with an apical crowding effect. (E) After the second three cycles of daily pulse therapy with orbital radiation, the extraocular muscles remained enlarged, and their signal intensity on STIR imaging was high. (F, G) After long-term repeated weekly pulse therapy, MRI showed improvement of the enlarged extraocular muscles on (F) May X + 5 (after weekly pulse therapy for the third exacerbation of TED) and (G) December X + 6 (during 0.5 g pulse therapy [every 2 weeks] after the fourth exacerbation of TED). The signal intensity of the extraocular muscles was decreased.

The patient had no history of smoking. She had a history of right facial nerve palsy at 39 years of age and surgery for ptosis of the right eyelid at 45 years of age. She had also been diagnosed with pemphigus foliaceus with an anti-desmoglein 1 antibody level of 130.0 U/mL (<20.0 U/mL) at 51 years of age and was treated with PSL. She had no history or symptoms of myasthenia gravis. She had an allergy to shrimp, crab, mackerel, and buckwheat. She also had diffuse goiter and TED. No skin eruption or pretibial myxedema was noted on physical examination. Her blood tests showed mild hyperthyroidism with high titers of anti-TSH receptor antibodies: free triiodothyronine, 6.05 pg/mL; FT4, 2.31 ng/dL; TSH, 0.026 mIU/L; TRAb (first-generation assay), 83.9%; TRAb (third-generation assay), 39.5 IU/L; TSAb, 5,924%; TgAb, <10.0 U/mL; and anti-thyroid peroxidase antibody, 2.0 U/mL. There was no evidence of hepatitis virus infection: hepatitis B surface antigen, <0.0001 (<0.005); hepatitis B core antibody, 0.1 (<1.0); and hepatitis C virus antibody, negative.

The patient developed orbital pain and visual loss in both eyes. Ophthalmological examinations at her first visit to our hospital (late June X + 3) showed swelling and erythema of both eyelids, conjunctival redness and edema, redness and swelling of the caruncle, wide palpebral apertures (right, 10 mm; left, 7 mm), exophthalmos (right, 27 mm; left, 25 mm), and optic disc edema. Her corrected visual acuity was 0.6 in the right eye and 0.3 in the left eye. She reported spontaneous and gaze-evoked pain in both eyes. Her clinical activity score (CAS) was 7 points. Orbital magnetic resonance imaging (MRI) showed significant enlargement of the extraocular muscles of both eyes with increased signal intensity on short tau inversion recovery imaging, assessed as previously reported [8]. Compression of the optic nerve was observed in the cone area of both eyes; therefore, the patient was diagnosed with DON (Fig. 2D). The next day, she was admitted to our hospital and received three cycles of 1 g daily pulse therapy. The T-SPOT.TB test (Oxford Immunotech, Ltd., Oxfordshire, UK) result on admission was positive. Chest computed tomography (CT) showed a tree-in-bud granular shadow in the upper left lobe and a tumor shadow in the superior anterior mediastinum (15.99 × 10.45 mm). The patient was diagnosed with latent pulmonary tuberculosis and a mediastinal tumor. She was treated with a combination of four anti-tuberculosis drugs (Isoniazid [INH] 300 mg, Rifampicin [RFP] 450 mg, Pyrazinamide 1.3 g, and Levofloxacin 500 mg) for 2 months, followed by two drugs (INH, RFP) for a further 4 months according to the recommendation of the tuberculosis review board. The mediastinal tumor was suspected to be a thymoma and was followed up. Her visual acuity improved to 0.9 in the right eye and 0.6 in the left eye 3 days after the initiation of pulse therapy. Both eyes improved to 1.2 on day 7. The diplopia, however, became exacerbated. After three cycles of the 1 g daily pulse therapy, the patient began oral PSL tapering therapy (PSL 20 mg/day for 4 weeks, 15 mg/day for 4 weeks, 10 mg/day for 4 weeks, 5 mg/day for 4 weeks, and 5 mg every 2 days for 4 weeks) and orbital radiation therapy (2 Gy/day 10 times, total of 20 Gy). She also received a palpebral injection of triamcinolone acetonide. However, eyelid swelling, conjunctival redness, and orbital pain persisted. On Dec X + 3, we explained to the patient that decompression surgery, and subsequent eye muscle and cosmetic eyelid surgeries, was one treatment option following pulse therapy. She preferred to undergo steroid therapy. Therefore, we selected 0.5 g of weekly pulse therapy (i.e., intravenous infusion of 0.5 g MP per week) under careful observation. Since then, her TED exacerbated four times (i.e., October X + 4, February X + 5, November X + 5, and January X + 7) with CAS ≥3. Each time, she received weekly pulse therapy with a favorable response (Fig. 1). The cumulative dose of MP in each course of weekly pulse therapy was 6 g. We also performed 0.5 g pulse therapy every 2 weeks from May X + 5 to June X + 5, from April X + 6 to January X + 7, and from May X + 7 to August X + 7. The total cumulative dose of MP was 59.5 g, which included the daily pulse therapy. In August X + 7, the exophthalmos recovered to 22 mm in the right eye and 21 mm in the left eye. The CAS decreased to 1–2. The TSAb level improved to 146% and the TRAb (third-generation assay) level to 1.6 IU/mL. Anti-desmoglein 1 antibody (3.0 U/mL) was negative. The patient experienced no side effects of pulse therapy. Her hyperthyroidism was treated with methimazole, and she maintained a euthyroid state. There was no change in the tree-in-bud granular shadow in the upper left lobe in the follow-up CT on December X + 6.

Discussion

The present report described the transition from hypothyroidism to GD and TED. Despite undergoing pulse therapy for moderate to severe TED, the patient’s condition progressed to DON. Even after her vision was restored by further pulse therapy, her eyelid swelling, conjunctival redness, exophthalmos, and diplopia persisted. Weekly pulse therapy was repeated for the exacerbation of TED; however, the orbital inflammation persisted for a considerable period.

Transition from hypothyroidism to GD and/or TED is rare. The reported rate of transition to GD ranges from 1.2% to 3.7% (26, 32), and 101 patients have been reported in the literature to date [9-48] (Table 1). The male-to-female ratio among these reports was 10:78. The mean age at transition from hypothyroidism to GD was 44.8 years, and the median duration of hypothyroidism before the shift to GD was 3 years (range, 1 month to 27 years). TED was reported in 17 patients (17%): one patient during the hypothyroid state and 16 patients at the time of GD. Only our case developed DON. In the hypothyroid state, TSAb was positive in 9 (41%) of 22 patients, and TSH-stimulation blocking antibody (TSBAb) was positive in 6 (40%) of 15 patients. In the hyperthyroid state, TSAb was positive in all 31 (100%) patients, and TSBAb was positive in 3 (17%) of 18 patients. Both TSAb and TSBAb were present in two patients [13, 48]. These findings suggest that the coexistence of both TSAb and TSBAb and the balance of these or the switch from TSBAb to TSAb are mechanisms underlying the transition of hypothyroidism to GD [14, 48, 49]. The presence of TSAb in the hypothyroid state may predict the development of GD. Our patient had a history of pemphigus foliaceus and had been treated with oral PSL. Furthermore, she had a mediastinal tumor, which may have affected her susceptibility to developing DON. Further studies are needed to investigate the possible mechanisms and proper management of the shift from hypothyroidism to GD, TED, and DON.

Table 1 Conversion to Graves’ disease from Hashimoto’s thyroiditis: reported cases

Ref.	Age (years)	Sex	HT stage			Duration of HT before GD Onset	GD stage			TED
			TRAb	TSAb	TSBAb		TRAb	TSAb	TSBAb
[9]	23	F	Neg	Pos	Neg	1year	Pos	Pos	Neg	Yes
[10]	48	F	Pos	Neg	Pos	2 years	Pos	Pos	Neg	No
[11]	40	M	Pos	Neg	Pos	1 year	Pos	Pos	Neg	No
[12]	23	F	Neg	Neg	Neg	1 year	Pos	Pos	Neg	No
	53	F	Neg	Neg	Neg	1 year	Pos	Pos	Neg	No
	28	F	Neg	Neg	Neg	2 years	Pos	Pos	Neg	No
	24	F	Neg	Neg	Neg	2 years	Pos	Pos	Neg	No
	38	F	Pos	Neg	Neg	1 year	Pos	Pos	Neg	No
	42	F	Neg	Neg	Neg	2 years	Pos	Pos	Neg	No
	38	F	Neg	Neg	Neg	ND	Pos	Pos	Neg	No
[13]	55	F	NA	NA	NA	3 years	NA	Pos	Pos	NA
[14]	40	F	Pos	Neg	Pos	2 years	Pos	Pos	Pos	No
[15]	50	F	NA	Pos	NA	12 years	Pos	Pos	NA	No
[16]	62	F	Pos	Pos	NA	2 months	Neg	Pos	Neg	No
[17]	40	F	Pos	Pos	Neg	3 years	Pos	Pos	Neg	No
[18]	60	M	NA	NA	NA	6 years	Pos	NA	NA	Yes
[19]	34	F	NA	Pos	NA	4 years	Pos	Pos	NA	No
[20]	46	F	Neg	NA	NA	5 years	Neg	NA	NA	NA
	48	F	ND	NA	NA	7 years	Pos	NA	NA	NA
	50	F	Neg	NA	NA	2.4 years	Pos	NA	NA	NA
	49	F	Neg	NA	NA	2 years	Pos	NA	NA	NA
[21]	31	F	NA	NA	NA	9 years	Pos	NA	NA	NA
[22]	80	F	NA	NA	NA	20 years	Pos	Pos	Neg	Yes
[23]	38	M	Pos	Neg	Pos	NA	NA	Pos	Neg	NA
	45	F	Pos	Neg	Pos	NA	NA	Pos	Neg	NA
[24]	52	F	NA	NA	NA	20 years	ND	Pos	NA	NA
[25]	36	F	NA	NA	NA	6 years	NA	NA	NA	NA
	46	F	NA	NA	NA	2 years	NA	NA	NA	NA
	43	F	NA	NA	NA	1 month	NA	NA	NA	NA
[26]*	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
[27]	60	M	NA	NA	NA	1 year	Pos	NA	NA	NA
[28]	41	F	NA	NA	NA	NA	NA	Pos	NA	NA
[29]	62	F	NA	NA	NA	25 years	Pos	NA	NA	No
[30]	61	F	NA	NA	NA	27 years	Pos	NA	NA	Yes
[31]	51	M	NA	NA	NA	6 years	Pos	NA	NA	NA
[32]	39**	F22 M2	NA	NA	NA	Mean 38 months	Pos	NA	NA	4/24***
[33]	54	F	NA	NA	NA	5 years	Pos	NA	NA	NA
[34]	41	F	NA	NA	NA	18 years	NA	Pos	NA	NA
	55	F	NA	NA	NA	16 years	NA	NA	NA	NA
[35]	30	F	NA	NA	NA	2 months	Pos	NA	NA	NA
[36]	56	F	NA	Pos	NA	16 years	NA	Pos	NA	Yes
[37]	25	F	NA	NA	NA	16 years	Pos	NA	NA	Yes
[38]	32	F	NA	NA	NA	5 years	NA	NA	NA	NA
[39]	25	F	NA	NA	NA	3 months	NA	Pos	NA	NA
[40]	56	F	NA	NA	NA	6 years	Pos	Pos	NA	NA
[41]	55	F	Neg	Neg	NA	16 years	Pos	Pos	NA	No
[42]	50	F	Neg	Pos	NA	2 months	Neg	Pos	NA	NA
[43]	33	F	NA	NA	NA	7 years	Pos	NA	NA	Yes
	57	M	NA	NA	NA	2.5 years	Pos	NA	NA	Yes
[44]	31	F	NA	NA	NA	10 years	Pos	NA	NA	NA
[45]	42**	F 11 M 1	NA	NA	NA	NA	Pos (12/12)	NA	NA	2/12****
[46]	42	M	NA	NA	NA	2 years	Pos	Pos	NA	No
[47]	66	F	NA	NA	NA	NA	Pos	Pos	NA	Yes
[48]	28	F	Pos	Pos	Pos	7 years	Pos	Pos	Pos	NA
our case	55	F	Pos	Pos	NA	11 months	Pos	Pos	NA	DON

HT, Hashimoto’s thyroiditis; GD, Graves’ disease; Ref., references; TRAb, thyrotropin receptor antibody; TSAb, thyroid stimulating antibody; TRBAb, thyroid stimulation blocking antibody; TED, thyroid eye disease; F, female; M, male; Neg, negative; Pos, positive; NA, not available;* 9 out of 35 patients (28 patients with Down syndrome and 7 female patients with Turner syndrome) and 4 out of 109 age-matched patients without Down syndrome or Turner syndrome developed conversion from HT to GD.; ** mean age; *** 4 patients had TED; **** 12 patients transited from HT to GD. 2 patients had TED.

DON, dysthyroid optic neuropathy

DON is the most severe type of TED and is associated with a high risk of blindness if left untreated. In Japan, the Treatment Guide for Thyroid-associated Ophthalmopathy [4] and the Diagnostic Criteria and Treatment Guidelines for Malignant Exophthalmos (Thyroid Eye Disease) [5] recommend an intravenous infusion of MP at 1 g/day for 3 consecutive days per week and/or radiation therapy to the orbital region. If there is no improvement within 2 weeks, orbital decompression surgery is recommended. In Japan, 22% to 38% of patients with DON undergo orbital decompression surgery [50, 51]. Several factors, such as female sex, older age, a long disease duration, unilateral significant DON, a history of resistance to steroid pulse therapy, unstable thyroid function, a high TRAb concentration, poor visual acuity, the presence of central diplopia, and the presence of corneal problems, are associated with the risk of needing urgent orbital decompression surgery. The severity of visual disturbance also affects the need for decompression surgery [50]. Although our patient had several risk factors (i.e., female sex, older age, and high TRAb concentration), her visual acuity was mildly disturbed and recovered within 1 week after 1g daily pulse therapy. We, therefore, performed three cycles of 1 g daily pulse therapy followed by oral PSL tapering therapy and orbital radiation with a combination of anti-tuberculosis drugs. However, the patient relapsed at least five times. Each time, we provided weekly pulse therapy. The total dose of methylprednisolone during each course was 4.5–6 g. The duration of disease activity typically ranges from 6 months to 2 years [1]. However, in our case, it may have exceeded 4 years.

MP pulse therapy is the first-line treatment for moderate to severe TED and very severe sight-threatening TED [4-7]. However, the cumulative dose should not exceed 8 g because of the potential for severe side effects, such as severe liver damage [6]. In Japan, severe liver dysfunction is found in 4% of patients during pulse therapy [52]. Therefore, the Japanese guidelines recommend that various examinations are performed before pulse therapy, such as the 75 g oral glucose tolerance test, upper gastrointestinal endoscopy, electrocardiography, liver function tests, hepatitis B surface antigen measurement, hepatitis B core antibody measurement, hepatitis C virus antibody measurement, the T-SPOT.TB test, and a bone mineral density test [4, 5]. However, the recent European Group on Graves’ Orbitopathy (EUGOGO) guidelines [7] and the consensus statement by the American thyroid association and the European thyroid association [53] recommend either combination therapy with an immunosuppressant or an increased dose of MP. Recent advances in the management of TED include the use of teprotumumab, an anti-insulin-like growth factor-1 receptor antibody [54, 55]. This therapy dramatically resolves proptosis and diplopia. Furthermore, there are reports that teprotumumab is also effective in patients with DON [56, 57]. Further studies are needed to elucidate the usefulness of teprotumumab in Japanese patients with TED and DON.

In conclusion, we experienced a case of progression from hypothyroidism to GD and DON, the most severe form of TED. Although her visual acuity recovered following two further cycles of daily pulse therapy, disease activity persisted for 4 years. TED exacerbated five times. Each time, the patient received weekly pulse therapy with no adverse reactions until her ophthalmopathy was relieved (Graphical Abstract). Careful monitoring by both endocrinologists and ophthalmologists using CAS, ophthalmological assessments, TSAb measurements, and orbital MRI are essential for making treatment decisions for TED.

Graphical Abstract 

Acknowledgment

We thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Disclosures

Y.H. serves as a consultant for Amgen Inc. The other authors have no conflicts of interest to declare.

Informed Consent

Written informed consent was obtained from the patient for publication of this case report.

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