A case of inappropriate thyroid-stimulating hormone secretion syndrome after thalidomide treatment

Abstract

Thalidomide is used for the management of several diseases, including the treatment of certain dermatological conditions. We report a case of thyroid dysfunction, characterized by a high serum thyroid-stimulating hormone (TSH) level accompanied by high free triiodothyronine (FT3) and free thyroxine (FT4), in a patient with preexisting hypothyroidism and human immunodeficiency virus (HIV) infection during thalidomide treatment. The case provides a novel pattern of thyroid dysfunction induced by thalidomide, differing from classical thyroid disease. We recommended a measurement of baseline thyroid function and TRAb before thalidomide treatment, every 2 weeks during the initial 1-3 months, and then monthly.

INTRODUCTION

Thalidomide was first developed in 1954 as a sedative drug, but was withdrawn 5 years later due to its teratogenic effects. Apart from its hypno-sedative effect, the substance also exhibits immunomodulatory, anti-inflammatory, anti-angiogenic, and anticancer properties.^[1,2] The properties of thalidomide inspired researchers to explore its mechanism of action and clinical range. In recent years, interest in thalidomide has resurfaced, such as its application in treating certain dermatological conditions that have remained unresponsive to conventional therapies. These include leprosy, HIV-associated aphthous ulceration, nodular prurigo, Behçet’s disease, systemic lupus erythematosus, actinic prurigo, and graft-versus-host disease.^[3] In this case, thalidomide was used to treat eczematous dermatitis in an HIV-positive patient. During therapy, the thyroid function was found to be abnormal.

CASE REPORT

A man aged 39 years visited our hospital on September 17, due to documented thyroid dysfunction for a month. More than 10 years ago, he was diagnosed with hypertension and chronic renal insufficiency. He received long-term treatment with traditional Chinese herbal medicine at external facilities, but with a poor therapeutic response. Subsequently, he was diagnosed with stage 5 chronic kidney disease (CKD) and initiated hemodialysis therapy.

Five years ago, the patient was confirmed to have hyperthyroidism and received oral methimazole (Thyrozol, Merck Healthcare (Jiangsu) company, Nantong, China) (10 mg/day) for over 1 year. Although thyroid function improved, it failed to normalize. Three years ago, he developed secondary hyperparathyroidism due to stage 5 CKD and long-term hemodialysis, which required surgical intervention: left thyroid lobectomy with isthmusectomy, partial right thyroid lobectomy, and parathyroidectomy. A 1/4 portion of the parathyroid tissue was transplanted subcutaneously in his right upper limb. Postoperatively, the patient experienced no limb weakness, numbness, convulsions, or other discomfort. He was maintained on long-term therapy with levothyroxine (Euthyrox, Merck Healthcare (Jiangsu) company, Nantong, China) 100 μg/125 μg alternately once daily and calcium carbonate (Caltrate, Haleon (Suzhou) Pharmaceutical company, Suzhou, China) 0.6 g twice daily. During this period, his thyroid function tests had been essentially normal: December 6, 2023: thyroid-stimulating hormone (TSH) 7.46 μIU/mL (normal range: 0.56-5.91 μIU/mL), free triiodothyronine (FT3) 4.8 pmol/L (normal range: 3.67-6.00 pmol/L), free thyroxine (FT4) 9.58 pmol/L (normal range: 7.86-21.10 pmol/L); July 6, 2024: TSH 0.43 μIU/mL, FT3 4.94 pmol/L, FT4 14.89 pmol/L.

Two years ago, he was diagnosed with HIV and has been receiving antiviral treatment with oral administration of Lamivudine (GlaxoSmithKline LLC, Suzhou, China) 50 mg and Dolutegravir (Tivicay, Delpharm Poznan S.A, Poznan, Poland) 50 mg once daily. On August 13, 2024 (a month before admission), he was diagnosed with eczematous dermatitis at another hospital. Treatments included applying compound dexamethasone acetate liniment (details unknown) and desonide cream (Huabang, Chongqing Huabang Pharmaceutical Company, Chongqing, China) externally, along with oral thalidomide (Fanyingting, Changzhou Pharmaceutical Factory, Changzhou, China) 100 mg/day. On September 06, 2024, the patient attended a follow-up visit at an external hospital, where abnormal thyroid function was detected: TSH 2.03 μIU/mL, FT3 12.96 pmol/L, and FT4 65.21 pmol/L. He discontinued thalidomide.

On September 18, 2024, the patient was admitted to our hospital with a history of post-thyroidectomy and abnormal thyroid function, where repeat thyroid function testing revealed TSH 6.39 μIU/mL, FT3 18.52 pmol/L, and FT4 80.32 pmol/L. On September 14, 2024 (4 days before admission), he self-discontinued levothyroxine. During hospitalization, we performed thyrotropin receptor antibody (TRAb), reverse triiodothyronine (rT3), and thyroglobulin (TG) testing in the patient: TRAb 40 IU/L (normal range: <1.9 IU/L); rT3 10 ng/mL (normal range: 0.20-0.95 ng/mL); and TG 7.38 μg/mL (normal range: 1.28-50.00 μg/mL). In contrast, his TRAb level was 0.69 IU/L on July 06, 2024. Notably, his thyroid peroxidase antibody (TPO-Ab) and TG antibody (TG-Ab) were normal: TPO-Ab 0.26 IU/mL (normal range: 0.00-5.61 IU/mL) and TG-Ab 1.81 IU/mL (normal range: 0.00-4.41 IU/mL). Pituitary MR plain scan plus contrast-enhanced imaging revealed a normal-shaped and sized pituitary gland (height: ~6 mm) with a 4 mm Rathke’s cleft cyst in the right upper margin. The remaining pituitary parenchyma showed uniform enhancement without abnormal non-enhancing lesions; the pituitary stalk was centered, and the high signal of the posterior pituitary gland was preserved [Figure 1]. The optic chiasm, cavernous sinuses, and other surrounding structures were unremarkable, ruling out structural lesions such as pituitary adenoma and craniopharyngioma.

Figure 1:

Pituitary magnetic resonance plain scan plus contrast-enhanced image: Small nodule at the right upper margin of the pituitary gland (consistent with a Rathke’s cleft cyst).

At discharge (23 September 2024), his thyroid hormone levels remained markedly elevated: TSH 47.35 μIU/mL, FT3 17.05 pmol/L, FT4 70.77 pmol/L. After discharge, he underwent thyroid function tests every 2 weeks. On November 7, 2024, his thyroid function transitioned to hypothyroidism, with TSH 333.61 μIU/mL, FT3 2.32 pmol/L, and FT4 6.66 pmol/L. At that point, the patient restarted taking levothyroxine 100 μg/day. Despite experiencing significant thyroid dysfunction during this period, the patient remained asymptomatic. In the following 6 months, the patient underwent a thyroid function test regularly, and the results were essentially normal. Trends of TSH, FT3, and FT4 before and after thalidomide treatment have been shown in Figure 2.

Figure 2:

Trends of TSH, FT3, and FT4 levels before and after thalidomide treatment. Arrows indicate key time points: (A) thalidomide initiation: 2024-08-13, (B) thalidomide discontinued: 2024-09-06, (C) levothyroxine withdrawal: 2024-09-14, and (D) levothyroxine restart: 2024-11-07. Normal reference ranges are shaded in the same color for each indicator.

DISCUSSION

This case presents a specific thyroid dysfunction in a patient with hypothyroidism after subtotal thyroidectomy, complicated by HIV infection and stage 5 CKD on long-term dialysis, following 1 month of thalidomide administration combined with topical glucocorticoids (dexamethasone and desonide cream). Its pathophysiological process forms a complete chain of “trigger-activation-exhaustion-regression,” which holds great clinical reference value.

Thalidomide, as the core triggering factor, exerts dual interference on the immune regulatory network and thyroid hormone metabolism, serving as the initiating link of the dysfunction. Clinical tests showed that after thalidomide treatment, the patient had elevated TRAb, while TPO-Ab, TG-Ab, and TG remained normal, with significantly increased rT3. This phenotype is highly consistent with the known pharmacological properties of thalidomide: as an immunomodulator, thalidomide can break thyroid immune tolerance.^[1] Against the background of immune deficiency caused by HIV infection, this effect is more likely to be amplified, inducing the specific production of TRAb (the absence of elevated other autoantibodies rules out primary autoimmune thyroiditis). Meanwhile, combined with the pathological basis of stage 5 CKD, uremic toxins inherently inhibit 5’-deiodinase activity,^[4] and thalidomide may synergistically exacerbate this metabolic disorder, leading to rT3 accumulation. The normal TG level indicates no obvious destructive damage to thyroid tissue, further excluding destructive thyroiditis.

Clinical test data in this instance indicate that abnormal activation of residual thyroid tissue and impaired pituitary negative feedback regulation collectively mediate the characteristic phenotype of synchronous elevation of hormones. The patient had insufficient reserve of residual follicular tissue after subtotal thyroidectomy, and the elevated TRAb, as a functional stimulatory factor, promoted the transient excessive secretion of FT3 and FT4. Pituitary magnetic-resonance imaging plain scan plus contrast-enhanced imaging ruled out structural lesions, yet the paradoxical phenomenon of synchronous elevation of TSH, FT3, and FT4 suggests that thalidomide may weaken the negative feedback inhibitory effect of thyroid hormones on TSH.

Regarding the concurrent use of topical dexamethasone and desonide cream, their systemic bioavailability is extremely low. Existing studies have not confirmed that topical glucocorticoids have a significant interference with the thyroid axis or the production of autoantibodies.^[5] Moreover, the thyroid dysfunction in this case showed a strong temporal correlation with thalidomide administration and discontinuation. Therefore, the primary pathogenic role of topical glucocorticoids can be excluded, and their impact on the overall pathophysiological process is minimal.

The pathophysiological outcome after thalidomide discontinuation further verifies its core role: Thalidomide has a half-life of ~5-7 h, and its pharmacological effects diminish after discontinuation, with gradual degradation of TRAb. In addition, the residual thyroid tissue, which had been overstimulated in the early stage, becomes functionally exhausted. Two months after drug discontinuation, the patient exhibited decreased FT3 and FT4 levels along with elevated TSH, returning to the baseline hypothyroid state after subtotal thyroidectomy.

Thalidomide and its analogs are used to treat multiple myeloma, myelodysplastic syndrome, and mantle cell lymphoma.^[6] During thalidomide treatment, the incidence of subclinical hypothyroidism is 20%, while overt hypothyroidism occurs in 7%.^[7] In a retrospective study of 170 patients receiving lenalidomide, both hypothyroidism and thyrotoxicosis were observed.^[8] Another series reported hypothyroidism induced by lenalidomide in patients with diffuse large B-cell lymphoma.^[9] In addition, two case reports describe hypothyroidism caused by pomalidomide.^[10,11] According to previous literature reports, hypothyroidism occurs commonly in patients who are treated with thalidomide. However, in this instance, we described a novel pattern of thyroid dysfunction induced by thalidomide, a particular scenario where FT3 and FT4 were elevated alongside TSH elevation. This pattern indeed differs from classical thyroid disease models and is rarely reported.

This is an unusual case from which we have gained substantial insights. First, a low initial dosage (25 mg/day) with gradual titration is recommended for thalidomide in HIV-positive patients with pre-existing thyroid disorders, to minimize fluctuations in thyroid function. Second, alternative agents (topical calcineurin inhibitors, low-dose systemic glucocorticoids, or pentoxifylline) may be considered for HIV-associated eczematous dermatitis to avoid thalidomide-related endocrine adverse effects. Last, a 2-3-month observation period is reasonable for asymptomatic patients with thalidomide-induced thyroid dysfunction, before initiating aggressive interventions.

CONCLUSION

In summary, this case clarifies the dynamic pathophysiological process of thalidomide-induced thyroid dysfunction in the context of multiple underlying diseases, supplementing the clinical spectrum in special populations. In line with clinical guideline recommendations, patients with such comorbidities should undergo baseline thyroid function and TRAb testing before thalidomide initiation. During the early stage of medication, re-examinations should be performed every 2 weeks, and the interval can be gradually extended monthly once the condition stabilizes. However, this case has several limitations: First, as a single case, the generalizability of the findings is limited and future prospective studies with larger sample sizes are needed to confirm this novel adverse effect of thalidomide; second, due to the patient’s external medical history, certain medical information is incomplete, including the duration of methimazole treatment 5 years ago, discontinuation time, and thyroid function status at that time.

AVAILABILITY OF DATA AND MATERIALS

The data analyzed in the current study were acquired from Hangzhou Xixi Hospital, affiliated with Zhejiang Chinese Medical University, which is not open to the public.

ABBREVIATIONS

CKD: Chronic kidney disease

FT3: Free triiodothyronine

FT4: Free thyroxine

HIV: Human immunodeficiency virus infection.

MR: Magnetic resonance

rT3: Reverse triiodothyronine

TG: Thyroglobulin

TG-Ab: Thyroglobulin antibody

TPO-Ab: Thyroid peroxidase antibody

TRAb: Thyrotropin receptor antibody

TSH: Thyroid-stimulating hormone

Funding Statement

FUNDING: The work was supported by the Construction Fund of Key Medical Disciplines of Hangzhou (2025HZGF09 and 2025HZZD13).

AUTHOR CONTRIBUTIONS

ZYJ: Drafted, edited, and reviewed the manuscript; CJ: Provided the data and materials and reviewed the manuscript. Both authors have read and agreed to the final version of the manuscript. Both authors are eligible for ICMJE authorship.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Ethical approval was obtained from the Ethics Committee of Hangzhou Xixi Hospital (Approval No.: 2025-081), in accordance with the principles of the Declaration of Helsinki. Written informed consent was provided by the patient for the publication of this case report and accompanying clinical data.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

EDITORIAL/PEER REVIEW STATEMENT

This manuscript underwent rigorous double-blind peer review with full anonymization. Two specialists assessed its scientific rigor and clarity, providing targeted revision suggestions. The first author revised the manuscript per comments, verified by co-authors.