Approach to thyroid disorders associated with immune checkpoint inhibitors and tyrosine kinase inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) have revolutionised the therapeutic landscape for a range of malignancies. However, their use is frequently associated with immune‐related adverse events (irAEs), particularly affecting the endocrine system. Thyroid dysfunction is the most common endocrine irAE, often occurring without symptoms, making routine thyroid function monitoring critical for early detection. Hypothyroidism is the predominant manifestation, though hyperthyroidism and central hypothyroidism due to immune‐mediated hypophysitis are also observed. Subclinical hypothyroidism may be monitored in the absence of symptoms; however, early treatment with cautious levothyroxine initiation is advised in patients with pre‐existing cardiac disease. When central hypothyroidism is suspected, adrenal insufficiency must be excluded before starting thyroid hormone therapy, and glucocorticoid replacement should precede levothyroxine to avoid precipitating an adrenal crisis. In cases of hyperthyroidism, transient thyroiditis and Graves disease should be considered. Persistent hyperthyroidism warrants further evaluation with thyroid receptor antibodies or a radionuclide thyroid scan. Management of endocrine irAEs depends on the severity (toxicity grade). Immunotherapy may be continued in mild cases but should be withheld temporarily in moderate to severe presentations. A multidisciplinary approach, particularly involving oncologists and endocrinologists, is essential to ensure optimal care and improve long‐term outcomes for patients.

Clinical case

A 56‐year‐old female with stage II lung adenocarcinoma underwent a left pneumonectomy and adjuvant cisplatin/vincristine in 2017. On recurrence, she received sequential therapies including gefitinib, then osimertinib, and was later enrolled in a clinical trial with cisplatin, pembrolizumab, and durvalumab ± tremelimumab. Baseline thyroid function was normal. After the first cycle of immunotherapy, routine monitoring revealed subclinical hyperthyroidism. She remained asymptomatic, but persistent biochemical hyperthyroidism led to an endocrine referral.

At review, she reported no tremor or palpitations but described increased exertional dyspnoea and 2‐kg weight loss without appetite change. Examination showed no goitre, tremor or eye signs; heart rate (HR) was 80 beats per minute (bpm) and regular. There was no personal or family history of thyroid disease. Thyroid receptor antibodies (TRAb) were negative. A radionuclide thyroid scan was planned.

Before this could be completed, she presented to hospital with 3 days of nausea and vomiting. She was clinically dehydrated, with blood pressure measurement of 108/83 mmHg, HR 91 bpm, and found to be hyponatraemic (plasma sodium 127 mmol/L). Investigations revealed a plasma cortisol concentration of 27 nmol/L, thyroid‐stimulating hormone (TSH) 0.48 mIU/L and free thyroxine (fT4) <5 pmol/L (Fig. 1). She was treated with intravenous fluids and commenced on hydrocortisone, resulting in normalisation of plasma sodium and blood pressure. Magnetic resonance imaging (MRI) pituitary showed no features of hypophysitis. Levothyroxine (LT4) was initiated 5 days after starting hydrocortisone. At follow‐up 2 weeks later, she was clinically well and normotensive.

Figure 1.

Timeline of presentation of thyroid dysfunction in setting of immunotherapy; initial subclinical hyperthyroidism progressed to overt hyperthyroidism (thyroiditis), followed by central hypothyroidism in the setting of pituitary hypophysitis.

Introduction

Immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) have revolutionised the therapeutic landscape for a range of malignancies, significantly improving progression‐free and overall survival, even in cancers historically considered untreatable. ¹ ICIs such as programmed cell death‐1 (PD‐1), programmed cell death ligand‐1 (PD‐L1) and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) inhibitors enhance T‐cell activity against tumour cells by removing inhibitory signals that suppress immune activation. ² TKIs, on the other hand, disrupt intracellular signalling pathways critical for tumour growth and angiogenesis. ³ Despite their therapeutic efficacy, these agents frequently induce immune‐related adverse events (irAEs), particularly within the endocrine system. Thyroid dysfunction is among the most prevalent endocrine irAEs, necessitating timely recognition and multidisciplinary management.

Epidemiology and clinical significance

Incidence by therapy class

See Table 1.

Table 1.

Incidence of thyroid dysfunction by therapy class

Agent class	Incidence of thyroid dysfunction (%)	Notes
Anti‐PD‐1/PD‐L1	6–9 4	Biphasic thyroiditis common; hypophysitis common with anti‐CTLA‐4 5
Anti‐CTLA‐4	~4 4
Combination therapy	~16 4
TKIs	6–70 6 (highest with sunitinib)	Gradual onset. Transient thyrotoxicosis precedes hypothyroidism 3

CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4; PD‐1, programmed cell death‐1; PD‐L1, programmed cell death ligand‐1; TKI, tyrosine kinase inhibitor.

Pathophysiology

ICIs induce thyroid dysfunction via autoimmune‐mediated inflammation. The unbridled immune activation targets thyroid tissue, resulting in thyroiditis. This is often a biphasic process: an initial hyperthyroid phase due to follicular cell destruction and hormone release, followed by hypothyroidism as hormone stores deplete and tissue damage progresses. ⁵

TKI‐induced dysfunction is primarily due to direct toxic effects on the thyroid gland or disruption of thyroid hormone synthesis and metabolism. ³

Risk factors

• Female sex (3:2 ratio) ³ , ⁷

• Pre‐existing thyroid autoimmunity (positive thyroid peroxidase (TPO) antibodies) ³

• Combination ICI therapy ⁴

• Longer duration of treatment ³ , ⁶

Clinical presentation

ICI‐associated thyroid dysfunction

Primary hypothyroidism is the most common endocrine irAE from ICIs.

ICI–induced thyroiditis typically follows a biphasic pattern, with thyrotoxicosis occurring 2–6 weeks after treatment initiation, followed by hypothyroidism within 3–9 months (Fig. 2). ⁷ Anti‐TPO and anti‐thyroglobulin antibodies are present in up to 60% of cases, suggesting an autoimmune component.

Figure 2.

Clinical course of immune checkpoint inhibitor‐associated thyroiditis and monitoring of thyroid function.

Symptoms include fatigue, weight gain, cold intolerance, dry skin and constipation. These can be subtle and easily mistaken for cancer‐related symptoms or treatment side effects.

Two thirds of cases require long‐term LT4 replacement. ⁴

Central hypothyroidism due to hypophysitis is more commonly associated with CTLA‐4 inhibitors. It tends to have a male‐predominant presentation. Clinical features may include fatigue, hyponatraemia, hypotension and evidence of secondary adrenal insufficiency, such as low adrenocorticotropic hormone (ACTH) and cortisol concentrations.

Hyperthyroidism, while less frequent, is increasingly recognised, particularly in the form of transient thyroiditis. Up to 10% of patients treated with combination ICI therapy may experience transient thyrotoxicosis. ⁴

TKI‐associated thyroid dysfunction

TKIs such as sunitinib, sorafenib and axitinib have been implicated in thyroid dysfunction. Sunitinib is associated with hypothyroidism in up to 60% of patients. ³ Transient thyrotoxicosis develops in approximately 20%–40% of cases and is often followed by hypothyroidism. ⁶ In patients who have undergone thyroidectomy, an increased requirement for LT4 may be observed. ³

Diagnostic workup

Monitoring thyroid function before starting ICI and TKI therapy is essential, as pre‐existing abnormalities can complicate the diagnosis of thyroid irAEs. Identifying the cause of thyroid dysfunction during treatment helps guide prognosis and alerts clinicians to other possible irAEs.

Baseline assessment

• TSH and fT4 prior to therapy.

• Consider checking TPO antibodies.

Monitoring during therapy

• Repeat TSH and fT4 every 4–6 weeks or before each treatment cycle.

• Monitor more frequently if symptomatic or abnormal results are noted (Fig. 2).

Red flags for pituitary involvement

Central hypothyroidism should be suspected if TSH is inappropriately normal or low despite low fT4. Evaluate with:

• Morning cortisol and ACTH

• Full pituitary panel: luteinising hormone (LH), follicle‐stimulating hormone, prolactin, insulin‐like growth factor 1 (IGF‐1), testosterone/oestradiol

• MRI pituitary, noting that MRI can be normal in ICI hypophysitis

Always exclude adrenal insufficiency before initiating levothyroxine to avoid precipitating adrenal crisis.

Management

Hypothyroidism

See Table 2.

Table 2.

Management of hypothyroidism

Clinical scenario	Recommended treatment
TSH >10 mIU/L + low fT4 (overt hypothyroidism)	Levothyroxine 1.6 μg/kg/day (<60 years, no ischaemic heart disease)
TSH 5–10 mIU/L, fT4 normal (subclinical hypothyroidism) + symptoms or TPO‐positive	Levothyroxine 25–75 μg/day
TSH 5–10 mIU/L, fT4 normal (subclinical hypothyroidism), asymptomatic, TPO‐negative	Monitor TFTs in 4–6 weeks
Any hypothyroidism (overt or subclinical) with heart disease/failure	Initiate low‐dose levothyroxine (25–50 μg/day)

Do not initiate thyroid hormone replacement until adrenal insufficiency is excluded.

fT4, free thyroxine; TPO, thyroid peroxidase; TSH, thyroid‐stimulating hormone.

Monitoring

Re‐assess TSH and fT4 every 4–6 weeks. Target TSH is typically 1–2.5 mIU/L, adjusted based on patient age and cardiac status.

Hyperthyroidism

See Table 3.

Table 3.

Management of hyperthyroidism

Clinical scenario	Management strategy
TSH↓, fT4 normal (subclinical hyperthyroidism)	Check free T3 (fT3). Repeat TFT prior to next cycle of therapy
TSH↓, fT4↑	Check fT3 and thyroid receptor antibodies (TRAb)
TRAb positive	Graves disease: Refer to endocrinology, initiate thioamides. Consider carbimazole 10–40 mg in divided doses, propylthiouracil 100–200 mg in divided doses
TRAb negative	Perform radionuclide thyroid scan
Thyroiditis	Symptomatic relief with beta blockers (e.g. propranolol); monitor TFTs every 2–3 weeks

fT4, free thyroxine; TSH, thyroid‐stimulating hormone.

Immunotherapy continuation based on toxicity grade ⁸

See Table 4.

Table 4.

Immunotherapy continuation based on toxicity grade

Toxicity grade	Definition	Management strategy
Grade 1	Asymptomatic or mild symptoms	Continue ICIs
Grade 2	Moderate symptoms, ADLs preserved	Hold ICIs until symptoms improve
Grade 3–4	Severe symptoms or life‐threatening	Hospitalisation, endocrine consultation required

ICI, immune checkpoint inhibitor; ADL, activities of daily living.

TKI‐related thyroid dysfunction

Monitoring should include baseline and periodic thyroid function test (TFTs) every 4–6 weeks during therapy. For cyclic TKI use (e.g. sunitinib), TFTs should be evaluated at the end of both the treatment and washout periods.

Management is similar to ICI‐induced thyroid dysfunction:

• Treat overt hypothyroidism with LT4.

• Transient thyrotoxicosis from thyroiditis requires only symptomatic therapy.

• Persistent hyperthyroidism should be evaluated for Graves disease, with endocrine consultation as required.

Practical pearls

• Patients often remain asymptomatic; routine TFTs are essential for early detection.

• Always exclude adrenal insufficiency in central hypothyroidism. TSH alone is insufficient in central hypothyroidism – always pair with fT4.

• MRI can be normal in ICI hypophysitis; clinical correlation is essential.

• In hypophysitis, prioritise adrenal replacement before thyroid hormone.

• Thyroid dysfunction typically does not warrant permanent discontinuation of cancer therapy.

• Collaborative care between oncologists and endocrinologists enhances patient outcomes.

Summary

Thyroid dysfunction is a common endocrine irAE associated with both ICIs and TKIs. Hypothyroidism predominates, often evolving from transient thyroiditis. Hyperthyroidism is less common but may herald an evolving autoimmune process. Routine thyroid function monitoring, timely hormone replacement and multidisciplinary care are essential. With vigilant management, most patients can safely continue their oncologic therapies.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.