Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors

Etiology

Agents employed as ICIs are frequently monoclonal antibodies that block proteins and receptors T cells use to attach to antigen-presenting cells. By blocking these proteins and receptors, ICIs inhibit a stop signal that negatively affects the immune system in normal circumstances. Inhibition of the stop signal allows the T cell to become activated, unleashing its response and instructing the T cell 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 stimulation of T cells. Cancer cells hide from the immune system using CTLA-4 pathways. The ICIs ipilimumab and tremelimumab are human monoclonal antibodies that prevent the inhibitory effect of CTLA-4 and allow T cells to become activated against cancer cells.

Another pathway affected by ICIs involves the programmed cell death-1 receptor (PD-1) and programmed death-ligand-1 (PDL-1).[5] PD-1 inhibits the overactivation of T cells during infections. Blockage of PD-1 allows a more robust immune response against certain types of cancer. The ICIs nivolumab and pembrolizumab are anti-PD-1 monoclonal antibodies.

Epidemiology

Endocrinopathies are one of the most commonly encountered IrAEs secondary to ICI use. The reported incidence of newly developed endocrinopathies in patients undergoing ICI treatment approximates 10%.[6][7] The presentation of the endocrinopathy is dictated by the type of ICI therapy; some endocrine organs are more affected by specific agents or combined therapies.

Endocrinopathies secondary to ICI use may include hypophysitis, thyroiditis, adrenal insufficiency, autoimmune diabetes, and calcium abnormalities. The most frequent endocrinopathies secondary to ICIs are hypothyroidism and hyperthyroidism, with a combined incidence of approximately 15%. These thyroid derangements are seen predominately when employing anti-PD-1 or anti-PD-L1 agents and are more common in females.[7]

Hypophysitis is most common in older male patients exposed to anti-CTLA-4 agents. Adrenal insufficiency has also been reported in older males, albeit less frequently than hypophysitis. Adrenal insufficiency appears to have a stronger association with the use of anti-PD-1 antibodies than with CTLA-4 inhibitors [7]. 

Endocrinopathies usually occur after at least 9 weeks of treatment with ICIs. Most adverse events happen within the first 9 months of initiating ICI therapy.[6] 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. 

Pathophysiology

The exact pathogenic mechanism of ICI-induced endocrine-related IrAEs is not well understood. However, overstimulation of T cells by ICIs can lead to reactive autoimmunity in cells that express the same receptors as cancer cells.

It is hypothesized that CTLA-4 is expressed in some pituitary cells and that PD-L1 is expressed in thyroid, pituitary, and pancreatic tissues. This expression opens the door to possible cross-reactivity and T-cell–mediated toxicity in these organs with ICIs.[4][8] Case reports have described adrenal and parathyroid disorders related to the use of monoclonal antibodies, but these endocrinopathies appear to be less common.[9][10] 

Another hypothesis is based on the concept of preexisting specific endocrine autoantibodies as conditioning for endocrine-related IrAEs. Labadzhyan et al performed a retrospective study over 36 weeks evaluating the presence of endocrine-related antibodies in adults before initiating ICI treatment with the development of endocrinopathies. Of the 60 patients evaluated, 11 were found to have preexisting endocrine autoantibodies and 3 seroconverted during ICI therapy. Endocrine autoantibodies were significantly associated with endocrine-related adverse effects, presenting the possibility of endocrine autoantibodies as predictive and follow-up markers for IrAEs.[11][12][13]

History and Physical

The presentation of IrAEs will depend on the specific endocrine gland and to what extent it is affected, as well as the dose and duration of the administered treatment. Patients with ICI-induced endocrinopathies may present with nonspecific symptoms challenging to distinguish from cancer symptoms or chemotherapy-related side effects.

The Thyroid

Approximately 2.6% to 6% of patients treated with ICIs will develop thyroid dysfunction. Thyroid endocrinopathies occur mainly in the setting of anti-PD-1, anti-PD-L1, and combined therapy at rates of 40%, 6% to 11%, and 20%, respectively.[7] Patients with ICI-induced thyroid dysfunction often present with mild-to-moderate symptoms of hypothyroidism or hyperthyroidism, including presentations similar to Hashimoto or Graves thyroiditis. However, symptoms of hypothyroidism are most frequent.[14] 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 will be needed.[7][15]

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. Symptoms of pituitary dysfunction usually develop 4 to 10 weeks after treatment initiation but can develop many as 22 weeks after treatment initiation or beyond treatment discontinuation.[16][17] Patients may present with hypophysitis, deficiencies in multiple hormonal axes, and enlargement of the adenohypophysis or as isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement.[18][19]. A male-to-female predominance of 4:1 has been reported for cases of hypophysitis.[20]

Once ACTH hyposecretion and corticotroph impairment develop, recovery of the hypothalamic-pituitary-adrenal axis may not occur with discontinuation of ICIs, resulting in long-term clinical repercussions and the need for chronic glucocorticoid treatment.[16] 

While secondary adrenal insufficiency is the most common pituitary-related IrAE, central hypothyroidism, and secondary hypogonadism are also commonly seen.[17] 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.[8][16][17]. There are rare case reports of ICI-induced neurohypophyseal dysfunction resulting in diabetes insipidus.[21]

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, all common in patients undergoing cancer treatment. While developing 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.[10]

Diabetes

The new onset of autoimmune diabetes is an uncommon complication reported in <1% of patients undergoing ICI therapy. Nonetheless, the presentation of autoimmune diabetes 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 are frequent signs of the initial presentation of ICI-induced autoimmune diabetes.[4][22]

Calcium Derangements

Isolated case reports have described acute symptomatic hypocalcemia from ICI-induced parathyroid hormone deficiency.[23] More research is needed to understand the exact mechanism of ICI-induced hypocalcemia; autoantibodies may activate the calcium-sensing receptor in some cases.[24] 

Evaluation

Regardless of the endocrinopathy, laboratory evaluation ideally should precede imaging studies. The measurement of specific hormone levels is dictated by the underlying endocrinopathy suspected.

The Thyroid Gland

The first step in evaluating suspected thyroid dysfunction is obtaining serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels. Surveillance of thyroid function should be performed in every patient undergoing treatment with ICIs.[6] A suppressed TSH with an elevated FT4 is characteristic of hyperthyroidism. Measurement of total serum triiodothyronine (TT3) levels may be helpful when FT4 levels are not elevated as expected, and T3 thyrotoxicosis is suspected. Contrarily, a high TSH with a low FT4 is a typical finding of primary hypothyroidism.[6][15] A thyroid ultrasound 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 F-18 fluorodeoxyglucose (FDG) uptake in the thyroid on positron emission tomography (PET/CT), and this imaging modality can be considered as a part of the evaluation.[25]

The Pituitary Gland

Given its potentially catastrophic consequences, the most essential step in the initial evaluation of pituitary gland dysfunction is to assess for adrenal insufficiency. While 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. An 8 AM cortisol level of <3 mcg/dL confirms the diagnosis of adrenal insufficiency in a patient with congruent signs and symptoms, and an 8 AM cortisol level >18 mcg/dL excludes it. Levels between 3 and 18 mcg/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.[10] Performing a cosyntropin-stimulation test can miss early cases of secondary adrenal insufficiency during acute hypophysitis, as the adrenal glands may still be able to respond to ACTH stimulation.

As opposed 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 should be measured in this circumstance. Evaluation of pituitary function should also include growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to exclude GH deficiency, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels along with testosterone levels in men and estrogen levels in premenopausal women are required to evaluate for secondary hypogonadism [6]. 

Magnetic resonance imaging (MRI) of the brain with a dedicated pituitary protocol should be obtained when pituitary involvement is suspected. Enlargement of the pituitary gland, post-contrast enhancement, and stalk thickening are typical findings.[7] However, the absence of imaging abnormalities does not exclude the diagnosis.[6]

Diabetes

In cases of hyperglycemia and insulin-dependent diabetes, measurement of hemoglobin A1c, serum blood glucose, and the autoantibodies, glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2), and zinc transporter-8 (ZnT8), can be obtained to establish the diagnosis. Autoantibodies are associated with the most severe hyperglycemia at presentation.[4] 

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 from Grades 1 to 5. Grade 1 represents very mild symptoms, and Grade 5 is reserved for patients who died due to complications. When endocrinopathies occur, ICIs may be withheld until hormone replacement has begun, especially in patients with more severe presentations.[26][27]

It is imperative to treat adrenal insufficiency before initiating other hormone supplementation. While central adrenal insufficiency is managed with glucocorticoids, primary adrenal insufficiency requires the addition of mineralocorticoids.[19][26](B3)

Replacement levothyroxine is indicated in cases of hypothyroidism. Beta-blockers are recommended for the symptomatic relief of thyrotoxicosis. Frequent measurement of thyroid function tests every 2 to 3 weeks is advised by the American Society of Clinical Oncology (ASCO) as thyrotoxicosis can be transient.[26] 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 hyperosmolar state.[7] 

ASCO recommends that all patients be closely monitored while taking hormonal supplementation, and the involvement of an endocrinologist should be considered to help with the dose titration and additional management, especially in patients with adrenal or pituitary involvement.[26]

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 treatment. These symptoms are nonspecific and resemble those of adrenal insufficiency or hypothyroidism. Patients diagnosed with cancer undergoing chemotherapy have a higher incidence of depression and anxiety related to their medical treatment; associated symptoms of fatigue, weight loss, and palpitations can mimic those of IrAEs. The diagnosis of endocrinopathies can be challenging if clinicians are unfamiliar with the potential toxic effect of ICIs.

Additionally, the high doses of corticosteroids frequently used in chemotherapy regimens may potentially suppress the hypothalamic-pituitary-adrenal axis and cause chronic secondary adrenal insufficiency, complicating the diagnosis of ICI-induced superimposed adrenal insufficiency. The baseline cortisol level of these patients will be unreliable.

Prognosis

The clinical resolution of an endocrinopathy will vary depending on the gland affected and the extent of the effect. Unfortunately, many endocrine-related adverse effects lead to chronic deficiencies requiring lifelong supplementation of affected hormones.[7] 

However, anterior pituitary hormones are not always affected at a similar magnitude as end-organ hormones, and recovery varies from axis to axis. While recovery of thyroid function has been described in the literature, other endocrine systems may be less likely to recover. Hypogonadism and ACTH-hyposecretion seem persistent in most described cases.[16] Insulin deficiency in autoimmune diabetes also appears permanent in most patients.[6] 

Although quality of life can be negatively affected in patients with endocrinopathies, most patients can have a reasonably normal life with hormone supplementation.

Complications

Depending on the affected organ, misdiagnosed or mismanaged patients can have catastrophic consequences from endocrine-related adverse events, as the development of adrenal insufficiency or insulin-dependent diabetes can rapidly progress and become life-threatening if it is not recognized and treated promptly.