Treatment-Refractory Hypothyroidism due to Proteinuria During Combined Immune Checkpoint and Tyrosine Kinase Inhibitor Therapy – A Case Report

Introduction

Immune checkpoint inhibitors (ICIs) have become a cornerstone of modern oncology. Their use has expanded rapidly since the first approval in 2011. ICIs are monoclonal antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein (PD-1) or its ligand PD-L1.^1,2 These agents enhance T-cell activation but can trigger immune-related adverse events (irAEs) affecting multiple organ systems. ³

Thyroid dysfunction is the most common endocrine irAE with a reported incidence of 42-53%. ³ ICI-related thyroid disease (ICI-TD) often presents as a transient thyroiditis that rapidly progresses to overt hypothyroidism and requires levothyroxine replacement. Most patients respond to weight-based dosing near 1.6 mcg/kg/day, with reported requirements ranging from 1.2 to 1.7 mcg/kg/day.^4-7

Although most patients respond to standard weight-based levothyroxine replacement in this setting, reasons for treatment-refractory hypothyroidism despite adherence are less well described. Common explanations include impaired absorption or drug interactions. Less commonly, increased renal loss of thyroid hormone may contribute.

We describe a patient with ICI-TD in whom the expected weight-based dose of levothyroxine was insufficient due to an uncommon cause. This case highlights the importance of considering renal loss of protein-bound thyroid hormone in patients receiving combination cancer treatments. We present this case in adherence with the CARE reporting checklist (see Supplemental Material 1). ⁸

Body (Case Presentation)

An 81-year-old non-Hispanic Asian woman with clear cell uterine cancer presented with weight loss and tremor two months after starting pembrolizumab, an ICI targeting PD-1, and lenvatinib, a multi-kinase inhibitor targeting vascular endothelial growth factor receptors. Thyroid function tests (TFTs) showed suppressed thyroid-stimulating hormone (TSH) with elevated free thyroxine (FT4) and triiodothyronine (T3), consistent with thyrotoxicosis. A fluorodeoxyglucose positron emission tomography scan (FDG PET) demonstrated new diffuse thyroidal FDG uptake consistent with thyroiditis (Figure 1). She was referred to endocrinology and we diagnosed ICI-related thyroid disease (ICI-TD).

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Figure 1.

18F-FDG PET imaging for restaging of uterine cancer. Maximum-intensity-projection (MIP) images (left panel) and transaxial fused PET/CT images (right panel) from a single patient demonstrate (A) normal thyroid gland without abnormal FDG uptake prior to initiation of lenvatinib and pembrolizumab, and (B) new diffuse thyroidal FDG uptake consistent with thyroiditis three months after initiation of lenvatinib and pembrolizumab coinciding with biochemical evidence of thyrotoxicosis.

We monitored thyroid function tests every 2 to 4 weeks. Given the mild and transient nature of her symptoms, we chose observation alone for initial management. We did not prescribe corticosteroids because she did not have thyroid pain. Antithyroid medications were not indicated because ICI-related thyroiditis is a destructive process. Her FT4 and T3 levels normalized within five weeks, and at nine weeks she developed overt hypothyroidism with elevated TSH and low thyroid hormone levels. Based on her weight, the full replacement dose was approximately 88 mcg daily. We initiated levothyroxine replacement and titrated the dose every 6 to 8 weeks. TSH remained elevated despite dose escalation to 150 mcg daily, nearly twice the expected weight-based dose (Figure 2).

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Figure 2.

Thyroid function following initiation of lenvatinib and pembrolizumab therapy. Serial measurements of thyroid-stimulating hormone (TSH) and free T4 (FT4) in a patient with uterine cancer demonstrated the development of thyrotoxicosis within 6 weeks of starting lenvatinib and pembrolizumab, followed by progression to hypothyroidism at 15 weeks. Levothyroxine therapy was initiated and resulted in normalization of FT4; however, TSH remained elevated despite dose escalation. Following the identification of proteinuria, lenvatinib was temporarily held leading to reduction in proteinuria and subsequent normalization of TSH. Lenvatinib was resumed at reduced dose, proteinuria stabilized, and the dose of levothyroxine needed to be decreased to maintain a euthyroid state.

Given the inadequate TSH response, we pursued further evaluation. The patient reported consistent adherence and appropriate administration of levothyroxine. Because the diagnosis of ICI-TD had already been established based on clinical presentation and imaging findings, we did not assess thyroid autoantibodies. Gastrointestinal causes, including celiac disease, were considered but were unlikely based on clinical assessment and testing.

We then evaluated for alternative causes and identified new-onset proteinuria shortly after starting the current combination cancer therapy. A 24-hour urine collection confirmed nephrotic-range proteinuria, and serum protein and albumin levels were below the reference range. Because thyroid hormone circulates primarily bound to plasma proteins, including thyroxine-binding globulin, these findings raised concern for urinary loss of protein-bound thyroid hormone.

Lenvatinib was held by oncology and proteinuria improved. Thyroid function normalized without a change in levothyroxine dose. As proteinuria decreased further, follow-up testing showed biochemical thyrotoxicosis, and we reduced the levothyroxine dose. Lenvatinib was later resumed at a reduced dose with ongoing monitoring. Over the following year, her thyroid function remained stable on a levothyroxine dose consistent with expected weight-based dosing.

Discussion

This case describes a patient with immune checkpoint inhibitor-related thyroid disease (ICI-TD) that was resistant to standard levothyroxine replacement. Despite appropriate dosing and adherence, TSH remained elevated. After further evaluation, we discovered she had significant proteinuria. With modification of lenvatinib dosing, proteinuria decreased and thyroid function normalized. These findings support urinary loss of protein-bound thyroid hormone as a key contributor to the increased levothyroxine requirement.

Thyroiditis is a diverse clinical entity with variable presentations and prognoses based on etiology (see Table 1). ICI-TD is one of the most common autoimmune reactions, though the exact mechanism by which this occurs remains unclear. It typically follows a biphasic course with transient thyrotoxicosis followed by hypothyroidism. ⁴ There are no formal recommendations for monitoring, but most expert opinions recommend some form of baseline screening prior to initiation, as well as periodic testing during treatment or if symptoms arise. ⁹

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Table 1.

Common Causes of Thyroiditis, Categorized by the Presence or Absence of Thyroid pain. Painful Thyroiditis is Typically Associated With Inflammation or Infection. Painless Forms are Often Auto-Immune, Drug-Induced, or Part of a Systemic Disease. Classification Aids in Differential Diagnosis and Guides Appropriate Management

Painful	Painless	Painful or painless
Infectious/Suppurative (bacterial, fungal, mycobacterial, septic)	Sporadic/Silent (postpartum, subacute lymphocytic)	Drug-induced (e.g., amiodarone, checkpoint inhibitors, interferon, lithium, tyrosine kinase inhibitors)
Subacute (de Quervain’s, granulomatous, nonsuppurative)	Chronic lymphocytic (Hashimoto’s)	Radiation-induced (radioiodine or external beam radiation)
​	​	Invasive (fibrous, IgG4-related, Riedel’s, sarcoidosis, amyloidosis, secondary tumors)
​	​	Trauma/palpation-induced10-12*

In patients with persistent TSH elevation despite adequate levothyroxine dosing, several mechanisms should be considered (see Table 2). These include nonadherence, impaired absorption, drug interactions, increased hormone loss, and laboratory assay interference. Gastrointestinal causes are often evaluated first. Renal loss of thyroid hormone is less commonly considered but may be clinically significant in the setting of proteinuria.

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Table 2.

Causes of Persistent TSH Elevation Despite Receiving Thyroid Hormone Replacement Therapy

Factor	Examples
Medication factors	• Insufficient dose
	• Missed doses
Increased thyroxine requirements	• Weight gain
	• Pregnancy
Decreased absorption	• Vomiting or diarrhea
	• Celiac disease
	• Inflammatory bowel disease
	• Altered GI anatomy (i.e., bariatric or other surgery of the GI tract)
Increased loss of thyroxine	• Nephrotic syndrome
Drug interactions	• Increased metabolism or clearance of thyroid hormone (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, mitotane, tyrosine kinase inhibitors)
	• Interference with absorption (e.g., calcium, iron, cholestyramine, sucralfate, proton pump inhibitors)
	• Alteration of bound hormone (e.g., estrogen, raloxifene, tamoxifen, methadone, mitotane)
Assay interference	• Biotin supplementation
	• Heterophile antibodies

Thyroid hormone circulates primarily bound to plasma proteins, including thyroxine-binding globulin, transthyretin, and albumin. In nephrotic states, urinary loss of these proteins can lead to increased loss of protein-bound hormone. This results in reduced circulating hormone and increased levothyroxine requirements.^13-17

In this patient, proteinuria developed shortly after initiation of lenvatinib. This drug is known to cause proteinuria through vascular endothelial growth factor pathway inhibition. ¹⁸ Improvement in proteinuria after holding lenvatinib was accompanied by normalization of thyroid function without a change in levothyroxine dose. This temporal relationship supports renal loss of thyroid hormone as the primary mechanism.

It is worth noting that lenvatinib has also been associated with hypothyroidism independent of proteinuria. Therefore, it is possible that her hypothyroidism was multifactorial and related to both ICI-TD as well as the direct effect of lenvatinib. However, the marked increase in levothyroxine requirement and subsequent improvement with reduction in proteinuria suggests that urinary hormone loss played a dominant role.

It should also be considered that there have been rare reports of nephrotic syndrome related to ICIs.^19-21 Conversely, nephrotic syndrome is a well-described side effect of anti-angiogenic drugs.^18,22 We felt ICI-related nephrotic syndrome was not likely given improvement in proteinuria despite continuation of pembrolizumab. Interestingly, Colombo et al (2024) found proteinuria in 29.6% of patients taking the combination of lenvatinib and pembrolizumab. ²³

This patient’s case highlights several practical considerations. Clinicians should suspect renal loss when levothyroxine requirements exceed expected weight-based dosing despite adherence. Evaluation for proteinuria should be considered in this setting. This is particularly important in patients receiving vascular endothelial growth factor inhibitors or other agents known to affect renal function.

As combination cancer therapies become more common, overlapping toxicities may complicate endocrine management. Future areas of interest include mechanistic studies to elucidate how ICIs and multi-kinase inhibitors influence thyroid hormone binding and renal clearance, as well as prospective studies to quantify the incidence of cancer treatments impacting thyroid function.

Conclusions

This case highlights the complexity of managing hypothyroidism in patients receiving combination cancer therapy. Although hypothyroidism developed after ICI-related thyroiditis, treatment was complicated by lenvatinib-associated proteinuria leading to increased thyroid hormone loss. Clinicians should consider renal loss when levothyroxine requirements exceed expected dosing. Multidisciplinary collaboration is essential to optimize care in patients receiving complex treatment regimens, particularly among specialties such as oncology, endocrinology, and nephrology.

Supplemental Material