Painless thyroiditis induced by pembrolizumab leading to depleted pituitary hypothyroidism: a case report and literature review

doi:10.21203/rs.3.rs-3643511/v1

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Case Report

Painless thyroiditis induced by pembrolizumab leading to depleted pituitary hypothyroidism: a case report and literature review

https://doi.org/10.21203/rs.3.rs-3643511/v1

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Introduction

Cases of hypothyroidism (referred to as hypothyroidism) induced by PD-1 inhibitor therapy are common in clinical practice, but cases of pituitary hypothyroidism induced by thyrotoxicosis have not been reported.

Case Report

We report a case of painless thyroiditis induced by the PD-1 inhibitor pablizumab in a patient with esophageal cancer with Hashimoto's disease combined with mild pituitary hypothyroidism, followed by depleting pituitary hypothyroidism induced by persistent severe thyroidal hypothyroidism.

Discussion/Conclusion

It is especially important to pay attention to the evolution of the disease in patients with pre-existing dual primary lesions, which are more complex.

hypothyroidism

pituitary hypothyroidism

vacuolar saddle

painless thyroiditis

Hashimoto's thyroiditis

Immunotherapy of tumors is a new paradigm for malignant tumors. In recent years, new antitumor drugs, immune checkpoint inhibitors (ICIs), have been used more and more widely. One class is programmed death1 (PD-1) inhibitors and the other class is programmed death ligand1 (PD-L1) inhibitors^{[1, 2]}. However, these drugs may cause immune-related adverse events (irAEs), and common endocrine-related irAEs include pituitary inflammation, thyroid dysfunction, diabetes mellitus, and hyperaldosteronism^{[3, 4]}. The common endocrine-related irAEs include pituitary inflammation, thyroid dysfunction, diabetes mellitus, and hyperalgesia. Among them, the most likely to cause thyroid dysfunction is PD-1 inhibitors ^[5]. Cases of hypothyroidism (referred to as hypothyroidism) induced by PD-1 inhibitor therapy are common in clinical practice, but cases of pituitary hypothyroidism induced by thyrotoxicosis have not been reported. In this paper, we report a case of painless thyroiditis induced by the PD-1 inhibitor pablizumab in a patient with esophageal cancer with Hashimoto's disease combined with mild pituitary hypothyroidism, followed by depleting pituitary hypothyroidism induced by persistent severe thyroidal hypothyroidism. To improve clinical awareness of endocrine adverse reactions that occur after the use of ICIs drugs, the following is reported.

The patient, male, 56 years old, was found to have mild thyroid function abnormalities during routine physical examination in 2019 (Table 1), thyroid ultrasound: consistent with the manifestation of Hashimoto's thyroiditis, which was not treated. 2022-04, esophageal cancer was found, and on 2022-04-15, he was treated with "pembrolizumab 200mg + paclitaxel albumin 400mg + carboplatin 400mg" chemotherapy combination immunotherapy. "Prior to immunotherapy, thyroid abnormalities worsened (Table 1) and the patient was not treated with medication. 21 days later, mild hyperthyroidism was detected when the patient underwent chemotherapy combined with immunotherapy again (Table 1). There was no pressure pain in the thyroid area. The patient was diagnosed with Hashimoto's disease with painless thyroiditis and was not treated. 21 days later, during the third chemotherapy combined with immunotherapy, mild hypothyroidism was detected and was treated with "L-Thyroxine tablets 50µg qd". 2022-07-07, thoracoscopic robotic assisted radical esophageal cancer resection (chest machine free + abdominal lumpectomy + tube gastric substitution) was performed. (left cervical anastomosis of esophagus). The pathology showed "high-grade intraepithelial neoplasia of squamous epithelium with no tumor involvement in the circumferential margin. Lymph nodes 1+/10 groups of 1+/15 were sent for examination and tumor metastasis was seen. Immunohistochemistry B2: CK5/6(+), CD56(-), CK(+), P40(+); C2: CD56(-), CK(+), P40(+), CK5/6(+)". Postoperatively, adjuvant chemotherapy with "pablizumab 200mg + carboplatin 400mg" was administered. The thyroid function was rechecked after surgery, and it was found that his hypothyroidism was progressively aggravated, so he was given "L-Thyroxine tablets 100µg qd". He was treated with "L-Thyroxine tablets 100µg qd". While systematically applying L-Thyroxine, he found that TSH decreased significantly, and T3 and T4 also decreased significantly. He was then seen in our department. Blood cortisol 8:00(COR): 179.64 ng/mL (52.70-224.50ng/mL), blood cortisol 16:00(COR): 65.4 ng/mL (34.40-167.60ng/mL), ACTH 8:00:49.80 ( 0.00–46.00) pg/mL, ACTH16:00: 24.10 pg/mL, folliculopoietin (FSH): 13.02 IU/L (1.40–8.10 IU/L), luteinizing hormone (LH): 3.06 IU/L (1.50–9.30 IU /L), estradiol (E2): 89pmol/L (< 146pmol/L), prolactin (PRL): 150.0mIU/L (45.0-375.0mIU/L), progesterone (P): 1.44nmol/L (0.89-3.88nmol/L), testosterone (To): 9.33 nmol/L (6.51–23.74 nmol/L). Liver and renal function electrolytes were normal. Pituitary MR suggested vacuolar pterygoid saddle (Fig. 1). The diagnosis was considered: painless thyroiditis induced by pablizumab leading to depleted pituitary hypothyroidism with vacuolated pteroid saddles. L-Thyroxine was increased to 150 mg qd. The results of the subsequent review were satisfactory.

Table 1

Thyroid function-related indicators before and after PD-1 inhibitors in this patient
	T3	T4	FT3	FT4	TSH	TPOAB	TGAB
19.10.1	1.25	51↓	5.59	17.08	0.938	1385↑	105↑
22.4.11	0.93↓	53.87↓	-	11.47	0.82	-	-	Before using PD-1 inhibitors
22.5.6	5.27↑	164.49↑	-	-	< 0.004↓	-	-	20d after use of PD-1 inhibitor
22.5.27	0.62↓	14.31↓	-	-	6.032↑	-	-	"L-Thyroxine 50µg qd" was administered 41d after PD-1 inhibitor
22.8.22	< 0.15↓	< 3.9↓	< 0.31↓	< 1.29↓	119.961↑	-	-	Postoperative PD-1 inhibitor with "L-Thyroxine 100µg qd"
22.9.3	-	-	1.74	0.68	55.05↑	-	-
22.9.22	0.39↓	31.2↓	1.21↓	0.46↓	71.86↑	240.7↑	551.7↑
22.10.27	0.67↓	68	2.76	1.29	2.36	213↑	347↑
22.11.21	0.85	64.1↓	3.37	1.55	0.06↓	361↑	202↑
23.1.27	0.76↓	45.8↓	2.9	1.09↓	0.08↓	228↑	419↑
23.3.6	1.2	77.70	6.51↓	23.67↓	0.013↓
T3: triiodothyronine: 0.92–2.79 nmol/L; T4: thyroxine: 58.1-140.6 nmol/L; FT3: free T3: 3.5–6.5 pmol/L; FT4: free T4: 11.5–22.7 pmol/L; TSH: thyroid-stimulating hormone: 0.55–4.78 mIU; TSH: thyroid-stimulating hormone: 0.55–4.78 mIU. free T4: 11.5-22.7pmol/L; TSH: thyroid-stimulating hormone: 0.55-4.78mIU/L; TPOAb: antithyroid peroxidase TPOAb: antithyroid peroxidase autoantibody: 0-60U/mL ; TgAb: antithyroglobulin autoantibody: 0-60U/mL

While ICIs kill tumors by modulating the immune response, over-activated immune cells may also lead to autoimmune damage, i.e., immune-related adverse reactions (irAEs)^[4].Studies^[6] have shown that pablizumab is more likely to cause thyroid injury than other ICIs. It is now generally accepted that the onset of thyroid dysfunction due to ICIs is mainly between 2 and 6 weeks after ICIs administration. The natural course of hypothyroidism is similar to that of painless thyroiditis^[4]. The natural course of the disease is similar to that of painless thyroiditis. Thyroiditis is a common disease, and the true prevalence of ICI-mediated thyroiditis has not been clearly reported. A retrospective study^[7] of 657 patients being treated with ICI found that 67% of patients developed painless thyroiditis.

The pathogenesis of thyroiditis caused by PD-1 inhibitors is unclear. It may be related to the patient's underlying thyroid disease, TSH levels, autoantibody titers (underlying autoimmune disease), and other factors^[8]. A prospective cohort study^[9] confirmed that patients with positive anti-thyroglobulin antibodies/thyroid peroxidase antibodies were more likely to develop thyroid dysfunction after PD-1 inhibitor therapy. However, some studies have also^[10] .It is believed that the mechanism of thyroid dysfunction triggered by PD-1 inhibitors involves T cells, natural killer cells and monocyte-related pathways, and is not related to thyroid autoantibodies.

ICI-associated pituitary inflammation occurs in 11–14% of patients treated with ICI, and the prevalence varies depending on the type of ICI^[11–13]. The main manifestations of pituitary inflammation are pituitary enlargement and hypopituitarism, mostly in the form of anterior hypopituitarism, with some involvement of the posterior pituitary, mostly secondary to hyperaldosteronism, and also secondary to hypothyroidism^[14]. The patient may also present with secondary hypothyroidism. In some patients recovering from pituitary inflammation, the pituitary gland may show vacuolation of the saddle^{[15, 16]}. The pituitary gland may show vacuolated saddle. The mean onset of ICIs-related pituitary inflammation is currently considered to be mainly at 9 weeks after ICIs administration, with PD-1/PD-L1-induced pituitary inflammation at 3–5 months after administration^[17], but is rare.

In this case, before pembrolizumab, T3 and T4 were below normal and tended to get progressively worse. TGAb and TPOAb were positive, but TSH was normal. The diagnosis should be considered: Hashimoto's disease with mild pituitary hypothyroidism^[18]. The diagnosis should have been Hashimoto's disease with mild pituitary hypothyroidism. Unfortunately, the test was not definitive at that time. The patient had painless thyroiditis induced by the use of pembrolizumab, which is a common adverse drug reaction. After a brief period of hyperthyroidism, the patient develops hypothyroidism, so we use L-Thyroxine replacement therapy^[18]. The special point of this case is that the starting labs support a mild pituitary hypothyroidism, however, the patient appeared to be a purely thyroidal hypothyroid with significant high TSH during the time of thyroiditis. However, during supplementation with L-Thyroxine, T3, T4 never reached the standard. TSH and T3, T4 did go into very low status. This cannot be explained by hypothyroidism. Combining the vacuolar saddle of the pituitary gland with normal reproductive hormone and adrenocorticotropic hormone indices, our interpretation is that the patient has isolated pituitary hypothyroidism (mild) due to the vacuolar saddle on top of Hashimoto's disease^[19]. The TSH secretory function reserve of both the thyroid and pituitary glands is inadequate. When pembrolizumab induces painless thyroiditis, the hyperthyroid phase is very low. The subsequent hypothyroid phase is very severe, with extremely low T3, T4 ,stimulating the secretion of hypothalamic TRH (thyrotropin-releasing hormone), which in turn promotes abnormal proliferation and secretion of pituitary TSH cells. However, the persistent malignant hyperplasia eventually depletes the already fragile pituitary TSH cell population, resulting in severe pituitary hypothyroidism. The sketch of lesion development is shown in Fig. 2.

The patient's preoperative PET-CT showed no distant metastases and no obvious lesions in the head, and there were no symptoms such as headache and blurred vision during all phases of his immunotherapy. Although we did not perform pituitary-related tests, this case does not look very much like pituitary inflammation. During the period of his severely increased TSH, although there was no pituitary MRI examination to confirm the time of vacuolation saddle occurrence, and the presence of hyperplasia and pituitary inflammation of the pituitary gland for a short period of time could not be denied. However, T3 and T4 were extremely low and did not improve with L-Thyroxine supplementation. The core etiology was considered to be the ongoing injury to the thyroid gland in Hashimoto's disease by pablizumab. The initial Hashimoto's disease with hypothyroidism, if caused by the thyroid gland, should be pituitary hyperplasia^[20]that should not be vacuolated pteroid saddle. Therefore, it is considered that there may be a combination of both thyroid and pituitary factors.

This patient has a reduced pituitary gland and a vacuolated butterfly saddle. Autoimmune thyroid disease with pituitary inflammation cannot be excluded, but it is difficult to confirm at this time. The patient had a month of severely reduced T3 and T4 and a significant increase in TSH, suggesting the presence of pituitary reactive hyperplasia^[20]. After replacement therapy with L-Thyroxine tablets, the proliferating pituitary cells retract so that the funnel hole and pituitary fossa can leave some empty space^[21].This can also produce a vacuolated pterygoid saddle. However, this could not be confirmed.

This patient had poor pituitary function prior to the use of PD-1 inhibitors, and the treatment did not exclude that PD-1 inhibitors caused damage to the pituitary gland itself. However, evidence for this is lacking. The TRH excitation test was not performed in this case, and the assessment of his pituitary and thyroid reserve function was inadequate.

This case suggests that thyroid and pituitary function needs to be evaluated before applying immune checkpoint inhibitors. It is especially important to pay attention to the evolution of the disease in patients with pre-existing dual primary lesions, which are more complex. Avoid inadequate hormonal supplementation.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Authors’ contributions

Ruona Chen drafted original draft and performed literature review of related topics. Yuqin Zhang significant contributions in acquisition of data and revision of manuscript. Yimeng Dai, Ming Zhong and Sina Du contributed to data curation and formal analysis. Haiying Zhao contributed to data analysis. Wei Li contributed to review and editing original draft.All authors read and approved the final manuscript.

Authors and Affiliations

Health Science Center, Ningbo University, Ningbo, China

Ruona Chen

Radiology Department, Ningbo Medical Center Lihuili Hospital, Ningbo, China

Yuqin Zhang

Health Science Center, Ningbo University, Ningbo, China

Yimeng Dai

Health Science Center, Ningbo University, Ningbo, China

Ming Zhong

Health Science Center, Ningbo University, Ningbo, China

Sina Du

Radiology Department, Ningbo Medical Center Lihuili Hospital, Ningbo, China

Haiying Zhao

Endocrine Department, Ningbo Medical Center Lihuili Hospital, Ningbo, China

Wei Li

Funding

No financial support.

Ethics approval and consent to participate

All methods were carried out in accordance with relevant guidelines and regulations. The patient provided written informed consent for data collection.

Consent for publication

Written Informed consent was also obtained from the patient for publication of this case report. “I understand that the text and any pictures published in the article will be freely available on the internet and may be seen by the general public.

Competing interests

The authors declare that they have no competing interests.

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No competing interests reported.

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Painless thyroiditis induced by pembrolizumab leading to depleted pituitary hypothyroidism: a case report and literature review

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Introduction

Case Report

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