Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors

Etiology

Agents used as ICIs are frequently monoclonal antibodies that block proteins and receptors T cells used to attach to antigen-presenting cells. By blocking these proteins and receptors, ICIs inhibit a stop signal that negatively affects the immune system under normal circumstances. Inhibition of the stop signal allows the T cell to become activated, unleashing its response and instructing it to attack cancer cells.[5] 

One example of a T-cell receptor blocked by an ICI is cytotoxic T lymphocyte–associated antigen-4 (CTLA-4). CTLA-4 normally antagonizes T-cell activity and prevents continuous T-cell stimulation. Cancer cells evade the immune system via CTLA-4 pathways. The ICIs ipilimumab and tremelimumab are human monoclonal antibodies that block the inhibitory effect of CTLA-4, allowing T cells to be activated against cancer cells.

Another pathway affected by ICIs involves the programmed cell death protein 1 (PD-1) receptor and programmed death ligand 1 (PD-L1).[5] PD-1 inhibits the overactivation of T cells during infections. Blocking PD-1 allows a more robust immune response against certain types of cancer. The ICIs nivolumab and pembrolizumab are anti–PD-1 monoclonal antibodies. An additional pathway affected by ICIs involves the lymphocyte activation gene-3 receptor, which normally suppresses T-cell activation, proliferation, and function. Blocking the lymphocyte activation gene-3 receptor, therefore, activates the T-cell response.[6]

Epidemiology

Endocrinopathies are among the most commonly encountered immune-related adverse events (IrAEs) associated with ICI use. The reported incidence of newly developed endocrinopathies in patients undergoing ICI treatment is approximately 10%.[7][8] The presentation of the endocrinopathy depends on the type of ICI therapy; certain endocrine organs are more affected by specific agents or by combined therapies.

Endocrinopathies associated with ICI use may include hypophysitis, thyroiditis, adrenalitis, autoimmune diabetes, and calcium abnormalities. The most frequent endocrinopathies associated with ICIs are hypothyroidism and hyperthyroidism due to thyroiditis, with a combined incidence of approximately 15% in adults. These thyroid derangements are seen predominantly with anti–PD-1 or anti–PD-L1 agents, are more commonly found in women, and they increase in incidence up to 20% with combination therapy involving anti–PD-1 and anti–CTLA-4 agents.[8]

Hypophysitis is more common in older men exposed to anti–CTLA-4 agents.[8][9] Hypophysitis may occur more often after 13 weeks of therapy and may be more common in patients treated with both PD-1 inhibitors and CTLA-4 inhibitors, with varying rates of resulting central adrenal insufficiency (up to 100%), central hypothyroidism (41%), and central hypogonadism (27%).[10] Primary adrenalitis can also cause adrenal insufficiency, but it is less common than hypophysitis and occurs more frequently with PD-1 inhibitors than CTLA-4 inhibitors.[8] Endocrinopathies usually occur after at least 9 weeks of treatment with ICIs, and most adverse events usually happen within the first 9 months after initiating ICI therapy.[7] However, endocrinopathies can emerge years after the initiation of ICI therapy, complicating the differentiation of the endocrinopathy from the adverse effects of other medications or cancer-related symptoms.[11]  

Children also present with similar complications after the use of ICIs in the pediatric cancer population. Thyroid disorders are reported in up to 17% of children treated with ICIs, with hypothyroidism being the most common presentation. Pituitary disorders are rare, reported in only 3% of treated children, versus autoimmune diabetes type 1, which is actually more common in the pediatric population exposed to this kind of cancer therapy than it is in adults, with studies showing percentages as high as 9%.[12][13]

Pathophysiology

The exact pathogenic mechanism of ICI-induced endocrine-related IrAEs is not well understood. However, the higher frequency of endocrine toxicities may be related to the presence of specialized proteins in endocrine tissues that are not otherwise found in other organs.[14] Additionally, overstimulation of T cells by ICIs can lead to reactive autoimmunity in cells that express the same receptors as cancer cells. Some experts hypothesize that CTLA-4 is expressed in some pituitary cells and that PD-L1 is expressed in thyroid, pituitary, and pancreatic tissues. Receptor expression increases the risk of ICI-induced cross-reactivity and T-cell–mediated toxicity in these organs.[4][15] Case reports have described adrenal and parathyroid disorders related to the use of monoclonal antibodies, but these endocrinopathies appear to be less common.[16][17] 

Another hypothesis posits preexisting specific endocrine autoantibodies as predisposing factors for endocrine-related immune-related adverse events. Labadzhyan et al performed a 36-week prospective study evaluating the presence of endocrine-related antibodies in adults before initiating ICI treatment and the development of endocrinopathies. Of the 60 patients evaluated, 11 had preexisting endocrine autoantibodies, and 3 seroconverted during ICI therapy. Endocrine autoantibodies were significantly associated with endocrine-related adverse effects, suggesting their potential as predictive as well as follow-up markers for immune-related adverse events.[18][19][20]

History and Physical

The presentation of IrAEs will depend on the specific endocrine gland affected, the extent of gland involvement, and the dose and duration of the administered treatment. Patients with ICI-induced endocrinopathies may present with nonspecific symptoms that are challenging to distinguish from cancer symptoms or chemotherapy-related adverse effects.

Thyroid Endocrinopathies

Thyroid endocrinopathies occur mainly in the setting of anti–PD-1, anti–PD-L1, or combined therapy at rates of 40%, 6% to 11%, and 20%, respectively.[8] Patients with ICI-induced thyroid dysfunction often present with mild to moderate symptoms of hypothyroidism or hyperthyroidism, including presentations similar to Hashimoto thyroiditis or Graves disease. However, the symptoms of hypothyroidism are most frequent.[21] Rarely, patients may present with symptoms suggestive of destructive thyroiditis, characterized by an initial transient thyrotoxicosis followed by subclinical or complete hypothyroidism and, finally, recovery of normal thyroid function. Unfortunately, full recovery of thyroid function may not occur, and long-term thyroxine supplementation may be needed.[8][22]

The Pituitary Gland

The pituitary gland is most commonly affected by anti–CTLA-4 antibodies or combined therapy and less frequently by anti–PD-1 or anti–PD-L1 antibodies. Monotherapy or combination therapy with anti–CTLA-4 antibodies also demonstrates a shorter time to the onset of hypophysitis (6-12 weeks after treatment initiation) compared with anti–PD-1 or anti–PD-L1 antibodies alone (16-26 weeks after treatment initiation). Symptoms of pituitary dysfunction can even develop after treatment discontinuation. [23][24][25][26][27] Patients may present with hypophysitis, deficiencies in multiple hormonal axes, and enlargement of the adenohypophysis.[28] These deficiencies are more commonly seen with CTLA-4 ICI monotherapy or combination therapy, or with isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement (usually associated with PD-1 or PD-L1 ICI monotherapy).[29][30] A 4:1 male to female predominance has been reported for hypophysitis.[25][26][31]

Once ACTH hyposecretion and corticotroph impairment develop, recovery of the hypothalamic-pituitary-adrenal axis may not occur after discontinuation of ICIs, leading to long-term clinical repercussions and the need for chronic glucocorticoid treatment.[23] Although secondary adrenal insufficiency is the most common pituitary-related irAE, central hypothyroidism and secondary hypogonadism are also commonly seen.[24] Headaches are the most common symptom of ICI-induced pituitary-related dysfunction reported in the literature, regardless of the cell line affected or hormonal deficiency.[15][23][24]. The posterior pituitary is usually spared; therefore, arginine vasopressin deficiency is not commonly seen, although rare case reports have described arginine vasopressin deficiency caused by suspected ICI-induced neurohypophyseal dysfunction.[26][32][33] Hyponatremia, on the other hand, has been reported in some cases after the use of ICIs, but it was related to other endocrine problems, including adrenal insufficiency from hypophysitis or primary adrenalitis, or sodium problems due to diabetes complications.[34]

The Adrenal Gland

Primary adrenal insufficiency resulting in glucocorticoid deficiency is a rare irAE, and the diagnosis is especially challenging if clinicians are unfamiliar with this endocrinopathy. Patients can present with nonspecific symptoms of fatigue, malaise, and muscle weakness, which are all common in patients undergoing cancer treatment. Although hyponatremia, hyperkalemia, hypoglycemia, or hyperpigmentation might distinguish primary adrenal insufficiency from other diagnoses, the absence of these signs and symptoms does not exclude adrenal dysfunction. Some patients with adrenal insufficiency can be completely asymptomatic until a physical or emotional stressor unmasks the disorder; failure to identify and treat an adrenal crisis can lead to life-threatening events and death.[17]

Diabetes Mellitus

The new onset of autoimmune diabetes mellitus is an uncommon complication reported in less than 1% of patients undergoing ICI therapy. Nonetheless, the presentation of autoimmune diabetes mellitus in those affected is usually severe; the onset of insulin deficiency is usually rapid and profound. Symptoms of hyperglycemia, such as polyuria and polydipsia, can develop quickly and become life-threatening or fulminant. Severe hyperglycemia with diabetic ketoacidosis, hyperosmolar hyperglycemic state, or a combination of both situations is a frequent sign of the initial presentation of ICI-induced autoimmune diabetes.[4][35]

Calcium Abnormalities

Isolated case reports have described acute symptomatic hypocalcemia from ICI-induced parathyroid hormone deficiency.[36] More research is needed to understand the exact mechanism of ICI-induced hypocalcemia; autoantibodies may activate the calcium-sensing receptor in some cases.[37] Patients will usually present with history and examination findings consistent with hypocalcemia, such as fatigue, abdominal discomfort, mental status changes, perioral numbness, and paresthesias.[38]

Evaluation

Regardless of the endocrinopathy, laboratory evaluation ideally should precede imaging studies. Specific hormone level measurements are dictated by the suspected underlying endocrinopathy. Targeted biochemical testing can then guide the need for organ-specific imaging.

The Thyroid Gland

The first step in evaluating suspected thyroid dysfunction is to obtain serum thyroid-stimulating hormone (TSH) and free thyroxine (FT₄) levels. Thyroid function should be monitored in all patients receiving ICIs.[7] A suppressed TSH with an elevated free T₄ is characteristic of hyperthyroidism. Measurement of total serum triiodothyronine (T₃) levels may be helpful when FT₄ levels are not elevated as expected, and T₃ thyrotoxicosis is suspected. Conversely, a high TSH with a low FT₄ is a typical finding of primary hypothyroidism.[7][22] Thyroid ultrasonography can better characterize glandular morphology and exclude thyroid nodules and other diagnoses in patients with presumptive hyperthyroidism. Most patients with ICI-induced thyroiditis have increased fluorine-18 fluorodeoxyglucose uptake in the thyroid on positron emission tomography (PET) and CT scans, and these imaging modalities can be considered part of the evaluation.[39]

The Pituitary Gland

Whereas asymptomatic screening for patients during anti–PD-1 or anti–PD-L1 ICI therapy is not routinely required, screening should be considered within the first 6 months for patients receiving CTLA-4 ICI monotherapy or combination therapy.[26][33] Given the potentially catastrophic consequences of adrenal insufficiency, the most essential step in the initial evaluation of pituitary gland dysfunction is to assess for adrenal insufficiency. Confirming the presence of adrenal insufficiency and treating it right away is also important to avoid precipitating an adrenal crisis. If coexisting central hypothyroidism is treated before the administration of glucocorticoid replacement, the adrenal crisis can be more severe. Although measuring early morning cortisol levels is usually the first step, treatment for adrenal insufficiency should not be delayed by a diagnostic evaluation if the patient presents with symptoms of an impending adrenal crisis.

Diagnosing ICI-induced hypophysitis in the setting of exogenous glucocorticoids, either as part of oncologic treatment or to treat other irAEs, can be challenging. In that setting, a glucocorticoid taper will be required before further testing. Once physiologic doses have been reached, further biochemical testing to assess for recovery should be performed, including ACTH, morning cortisol, and in some cases, a 250-µg ACTH stimulation test. Evidence of persistent secondary adrenal insufficiency would confirm the presence of hypophysitis rather than glucocorticoid-induced adrenal insufficiency.[26]  

An 8 AM cortisol level less than 3 µg/dL confirms the diagnosis of adrenal insufficiency in a patient with congruent signs and symptoms, and an 8 AM cortisol level greater than 18 µg/dL excludes adrenal insufficiency. Levels between 3 and 18 µg/dL are harder to interpret; complete or partial adrenal insufficiency remains a possible diagnosis. A confirmatory cosyntropin stimulation test can be performed in these cases to confirm a diagnosis of adrenal insufficiency. A low or normal serum ACTH level is expected in central adrenal insufficiency, whereas a high serum ACTH level is characteristic of primary adrenal insufficiency.[17] Performing a cosyntropin stimulation test may miss early cases of secondary adrenal insufficiency during acute hypophysitis because the adrenal glands may still respond to ACTH stimulation.

In contrast to primary hypothyroidism, TSH has no diagnostic value in secondary hypothyroidism; either low or high TSH levels can be seen despite thyroid hormone deficiency. A serum FT₄ level should be measured in this circumstance. Evaluation of pituitary function should also include growth hormone and insulin-like growth factor 1 levels to exclude growth hormone deficiency. Luteinizing hormone and follicle-stimulating hormone levels, along with testosterone in men and estrogen in premenopausal women, should be checked for the evaluation of secondary hypogonadism.[7]

MRI of the brain with a dedicated pituitary protocol should be obtained when pituitary involvement is suspected. Enlargement of the pituitary gland, postcontrast enhancement, and stalk thickening are typical findings.[8] However, the absence of imaging abnormalities does not rule out the diagnosis, particularly because pituitary enlargement on MRI is often absent after treatment with PD-1 or PD-L1 ICIs.[7][40]

The Adrenal Gland

If ACTH is markedly elevated during evaluation for adrenal insufficiency, further evaluation of primary adrenal insufficiency may include assessment for hyponatremia, hyperkalemia, and elevated renin levels. Dedicated adrenal imaging is not strictly necessary. However, a CT scan may help evaluate for other causes of primary adrenal insufficiency, such as hemorrhage or metastasis.[41][42]

Diabetes Mellitus

In cases of hyperglycemia and insulin-dependent diabetes, measurements of hemoglobin A1c, serum glucose, and autoantibodies against glutamic acid decarboxylase, islet antigen-2, and zinc transporter-8 can be obtained to establish the diagnosis. Autoantibodies are associated with the most severe hyperglycemia at presentation.[4] The HLA-DR4 allele has been associated with both type 1 and ICI-induced diabetes mellitus; however, HLA-DR4 testing is not yet commonly recommended as part of the laboratory evaluation.[43]

Treatment / Management

Independent of the endocrine organ affected, ICI-induced endocrine-related adverse events are classified by the severity of signs and symptoms. Treatment should be individualized for each specific case. The severity of signs and symptoms is classified into grades 1 to 5. Grade 1 represents very mild symptoms, and grade 5 is reserved for patients who die due to complications. When endocrinopathies occur, ICIs may be withheld until hormone replacement has begun, especially in patients with more severe presentations.[41][42]

Adrenal insufficiency must be treated before initiating other hormone supplementation. While central adrenal insufficiency is treated with glucocorticoids, primary adrenal insufficiency requires the addition of a mineralocorticoid such as fludrocortisone.[30][42] Once adrenal insufficiency has been treated, replacement of other hypophysitis-related deficiencies is also warranted. Notably, growth hormone replacement is not recommended in the setting of active malignant neoplasm due to a lack of safety data and concern for a procarcinogenic effect. Results from some studies demonstrated recovery of central hypothyroidism and central hypogonadism; however, central adrenal insufficiency remains permanent in most of the affected cases.[26][40][44] Pituitary enlargement typically resolves within 12 weeks, so persistence beyond this duration should raise concern for alternative etiologies, including pituitary metastases.[26][40](B2)

Replacement levothyroxine is indicated in cases of hypothyroidism. β-Blockers are recommended for the symptomatic relief of thyrotoxicosis. The American Society of Clinical Oncology recommends measuring thyroid function tests every 2 to 3 weeks because thyrotoxicosis can be transient.[42] Hyperthyroidism that persists beyond 6 weeks is usually managed with medical thyroid suppression. For patients with autoimmune diabetes, insulin is the preferred therapy, especially in cases of diabetic ketoacidosis or a hyperosmolar hyperglycemic state.[8] In cases of hypocalcemia and hypoparathyroidism, long-term treatment with calcium and calcitriol has been successful.[38] The American Society of Clinical Oncology recommends that all patients be closely monitored while receiving hormonal supplementation and that an endocrinologist be involved to assist with dose titration and additional treatment, especially in patients with adrenal or pituitary involvement.[42]

Differential Diagnosis

The signs and symptoms associated with endocrinopathies can be vague and misleading. Many patients undergoing cancer treatment develop fatigue, malaise, generalized weakness, or myopathies secondary to chemotherapy. All these presentations are nonspecific and resemble those of adrenal insufficiency or hypothyroidism. Patients with cancer undergoing chemotherapy have a higher incidence of depression and anxiety related to cancer treatment; symptoms such as fatigue, weight loss, and palpitations may mimic those of immune-related adverse events. The diagnosis of endocrinopathies can be challenging if clinicians are unfamiliar with the potential toxic effects of ICIs. Additionally, high-dose corticosteroids frequently used in chemotherapy regimens may suppress the hypothalamic-pituitary-adrenal axis and cause chronic secondary adrenal insufficiency, complicating the diagnosis of superimposed ICI-induced adrenal insufficiency. The baseline cortisol level of these patients will be unreliable, as noted previously.

Prognosis

Clinical resolution of an endocrinopathy will vary depending on the affected gland and the extent of involvement. Unfortunately, many endocrine-related adverse effects lead to chronic deficiencies requiring lifelong supplementation of affected hormones.[8] However, anterior pituitary hormones are not always affected to the same magnitude as end-organ hormones, and recovery varies from axis to axis. Although recovery of thyroid function has been described in the literature, other endocrine systems may be less likely to recover. Hypogonadism and ACTH hyposecretion appear to be persistent in most described cases.[23] Insulin deficiency in autoimmune diabetes mellitus also appears permanent in most patients.[7] Although the overall quality of life can be negatively affected in patients with endocrinopathies, most patients can have a reasonably normal life with the recommended hormone supplementation and close monitoring.

Complications

Depending on the affected organ, delayed diagnosis or inappropriate treatment may have catastrophic consequences for patients with endocrine-related adverse events, because adrenal insufficiency or insulin-dependent diabetes can rapidly progress and become life-threatening if they don't have prompt recognition and treatment.