Secondary Adrenal Insufficiency and Multisystem Endocrinopathy Following Immune Checkpoint Inhibitor Therapy

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, including malignant melanoma. However, ICIs are associated with immune-related adverse events (irAEs), including hypophysitis, secondary adrenal insufficiency, thyroid disorders, and insulin-dependent diabetes. We present the case of a 60-year-old male with a history of autoimmune disorders, including primary hypothyroidism and giant-cell arteritis, who developed diabetes mellitus requiring insulin therapy after 6 weeks of treatment, eosinophilic asthma after 10 weeks, and who was admitted after 28 weeks of therapy with secondary adrenal insufficiency due to suspected ICI-associated isolated adrenocorticotrophic hormone (ACTH) deficiency. Pituitary magnetic resonance imaging showed no abnormalities. After several surgeries for melanoma and basal cell carcinoma, his current treatment includes hydrocortisone, levothyroxine, and insulin therapy. This case highlights the complexities in diagnosing and managing endocrinopathies associated with ICI therapy. As ICIs become more widely used, endocrine irAEs such as hypophysitis and isolated ACTH deficiency are expected to become increasingly common. A multidisciplinary approach is key to minimizing complications. While endocrine irAEs may require prompt hormone replacement, they rarely justify discontinuation of ICI therapy, whose benefits often outweigh the risks.

INTRODUCTION

The emergence of immune checkpoint inhibitors (ICIs) has significantly advanced the treatment paradigms for various malignancies, including malignant melanoma. ICIs, including cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors, and programmed death-ligand 1 (PD-L1) inhibitors, have improved patient survival and disease control. Despite their clinical benefits, ICIs are associated with immune-related adverse events (irAEs) affecting multiple organ systems. Among endocrine irAEs, hypophysitis and secondary adrenal insufficiency are particularly important, as they are uncommon yet clinically challenging to diagnose and manage.

Incidence and clinical spectrum of immune checkpoint inhibitor-induced endocrine immune-related side effects

The incidence of hypophysitis varies significantly with the type of ICIs administered. CTLA-4 inhibitors, like ipilimumab, are predominantly associated with a higher incidence of hypophysitis compared to PD-1 and PD-L1 inhibitors (nivolumab and pembrolizumab).[1,2] The combination of CTLA-4 and PD-1 inhibitors leads to an additive increase in incidence. The reported incidence of hypophysitis in patients undergoing ICI therapy can reach up to 18%, according to various studies. Notably, this condition is more common in males, with a male-to-female ratio of 4:1.[3] Yang et al. reported a higher frequency of endocrine irAEs in women, with most events involving thyroid dysfunction.[4] The onset of irAEs usually occurs within 7 weeks from the start of ipilimumab treatment and 10–15 weeks for nivolumab.[5]

Hypophysitis associated with ICI is characterized by immune-mediated inflammation of the pituitary gland, which can result in panhypopituitarism.[6]

Hypophysitis may result from type II and IV hypersensitivity reactions, with ICI acting as neoantigens that provoke autoimmune destruction of pituitary cells.[7,8] The presence of anti-pituitary antibodies has been confirmed in numerous studies, supporting the autoimmune hypothesis.[9]

Symptoms of endocrine disorders can emerge shortly after starting ICI therapy, during treatment, or even after discontinuation of therapy. These symptoms vary widely depending on the affected endocrine gland and can be difficult to distinguish from those caused by the tumor or concurrent therapies. The common endocrine disorders associated with ICI therapy include hypophysitis, thyroid disorders (Graves’ disease, thyroiditis, hypothyroidism, and thyroid eye disease), adrenal insufficiency, diabetes mellitus (DM), hypoparathyroidism, and polyendocrine syndromes.[10]

Diagnostic challenges in immune checkpoint inhibitor-induced secondary adrenal insufficiency

The clinical presentation of ICI-induced hypophysitis might include nonspecific symptoms such as headache, fatigue, and visual disturbances. These manifestations often mask the underlying hypocortisolism. The severity of hypophysitis can range from subtle symptoms to severe presentations, including intense headaches or life-threatening pituitary crisis, making diagnosis challenging. Central diabetes insipidus is less common, but can occur depending on the extent of pituitary involvement.[3,10]

Proposed diagnostic classification and criteria for ICI-induced pituitary disorders were suggested in 2023 and include hypophysitis, hypopituitarism, and isolated adrenocorticotrophic hormone (ACTH) deficiency.[11]

Hypophysitis is diagnosed based on pituitary enlargement on magnetic resonance imaging (MRI), with or without associated symptoms such as headache, or by the presence of new-onset hypopituitarism.

Hypopituitarism is diagnosed when deficiencies of two or more anterior pituitary gland hormones are present. This is confirmed by low concentrations of anterior pituitary hormones (ACTH, thyroid-stimulating hormone [TSH], and luteinizing hormone/follicle-stimulating hormone with either elevated or reduced prolactin concentrations) together with decreased concentrations of peripheral hormones, including morning cortisol, free thyroxine (fT4), testosterone in males, or estrogen in females.

Isolated ACTH deficiency represents selective corticotroph dysfunction without involvement of other pituitary axes. In patients receiving glucocorticoid therapy, interpretation of ACTH and morning cortisol concentrations may be challenging.

Management strategies of immune checkpoint inhibitor-induced endocrine immune-related adverse events

The Current European Society of Endocrinology (ESE) and American Association of Clinical Endocrinology guidelines provide recommendations for the evaluation and management of suspected ICI-related adrenal insufficiency and hypophysitis.[10,12] In patients presenting with severe headaches or neurological symptoms, pituitary MRI is recommended to assess for pituitary enlargement and exclude alternative causes such as metastases. However, when adrenal crisis is suspected, glucocorticoid therapy should be initiated immediately without delaying treatment for imaging results.[10]

High-dose glucocorticoids (>7.5 mg/day of oral prednisone or its equivalent) are reserved for selected situations, including hypophysitis with severe untreatable headache or pituitary enlargement and mass effect. In most patients, physiological glucocorticoid replacement is recommended, as unnecessary high-dose therapy may adversely affect oncological outcomes.[13]

Glucocorticoid replacement should always precede thyroid hormone therapy to prevent adrenal crisis. Mineralocorticoid replacement should be initiated in primary adrenal insufficiency.

Many studies demonstrated a high prevalence of hypothyroidism and thyrotoxicosis (often with a destructive pattern) in patients on ICI therapy. Unlike adrenal insufficiency, this condition is often reversible. Patients with preexisting thyroid disorders are at higher risk of developing thyroid irAEs during ICI treatment.[2,4]

CASE REPORT

A 60-year-old male underwent surgical excision of melanoma on his left foot, followed by initiation of nivolumab. His medical history was notable for hypertension, prediabetes, giant-cell arteritis (in remission), epilepsy (on phenytoin), and primary hypothyroidism (secondary to autoimmune Hashimoto’s thyroiditis). At baseline, he was receiving levothyroxine 150 µg daily and valsartan 80 mg daily.

After several weeks of nivolumab therapy, the patient developed symptomatic hyperglycemia requiring hospital admission, and a diagnosis of DM was confirmed [Table 1]. Insulin therapy was required to control this new condition. Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state were excluded. Antibody testing for latent autoimmune diabetes in adults (LADA) was negative, including glutamic acid decarboxylase (GAD), islet cell, insulin receptor, zinc transporter 8, and insulin antibodies. The patient was discharged on combined metformin and dipeptidyl peptidase-4 inhibitor therapy in addition to basal insulin.

Table 1.

Timeline of immune-related adverse events

Time from nivolumab initiation	Clinical event
Prior to therapy	History of prediabetes
Week 0	Start therapy
Week 6	Admission with symptomatic hyperglycemia, diagnosed with DM
Week 10	Eosinophilic asthma and rhinitis
Week 16	Fatigue and episodes of low BP, cessation of antihypertensive therapy
Week 23	Cholecystectomy
Week 28	Diagnosed with secondary adrenal insufficiency and DKA
Week 38	Deterioration of eosinophilic asthma
Week 40	Discontinued treatment after 12 sessions
Week 54	Left upper arm melanoma and right ear basal cell carcinoma, surgery
Week 63	Left thigh melanoma, surgery
Week 135	Right thigh melanoma, surgery

BP=Blood pressure, DKA=Diabetic ketoacidosis, DM=Diabetes mellitus

One month after discharge, the patient developed eosinophilic asthma and rhinitis associated with nivolumab therapy, managed with inhaled and nasal corticosteroids.

A few months later, he exhibited increasing signs of fatigue and episodes of low blood pressure, prompting cessation of his antihypertensive medication. These symptoms were initially thought to be related to his skin disease and treatment itself, as well as to his complex medical history. Given the risk of adrenal insufficiency on nivolumab treatment, morning cortisol concentrations were regularly checked. Despite all the concentrations of cortisol (and ACTH) within the reference range (217–392 nmol/L), a short Synacthen test was requested, but was not performed.

Eventually, the patient was admitted to the intensive care unit with symptoms of extreme fatigue, abdominal pain, hypotension, hyponatremia, and severe headache.

On admission, laboratory results revealed hyponatremia (sodium: 119 mmol/L), low ACTH (5.7 pg/mL; reference range: 7.2–63.3 pg/mL), and baseline cortisol of 135 nmol/L with no significant increase after Synacthen administration, peaking at only 137 nmol/L in 30 min and 217.5 nmol/L in 60 min. Additional tests showed random glucose 6.95 mmol/L, bicarbonate 12.05 mmol/L, pH 7.26, lactate 2.6 mmol/L, and blood ketones 6.1 mmol/L. Serum calcium was 2.28 mmol/L, potassium 4.3 was mmol/L, and chloride was 89 mmol/L. Liver enzymes were mildly elevated (alanine aminotransferase: 59 U/L and aspartate aminotransferase: 84 U/L). Renal function was preserved (estimated glomerular filtration rate: 99 mL/min, urea 3.1 mmol/L, and creatinine 67 µmol/L). Full blood count revealed eosinophilia (1.9 × 10³/µL) and C-reactive protein was elevated at 14.9 mg/L. TSH was 2.3 mIU/L and HbA1c was 8.3%.

Given the clinical presentation and laboratory findings, a diagnosis of secondary adrenal insufficiency most consistent with ICI-associated isolated ACTH deficiency was made. The presence of ketones in the blood and urine as well as low bicarbonate concentrations supported the diagnosis of ketoacidosis. The DKA protocol was initiated with intravenous hydrocortisone therapy. His blood pressure was low and responded to fludrocortisone, which was discontinued subsequently.

Imaging studies, including a MRI of the brain and pituitary gland, revealed no clear abnormalities. Repeated LADA antibodies were negative; however, the patient was considered to have ICI-associated insulin-dependent DM complicated by ketoacidosis.

The patient remained hospitalized for 5 days. Over this period, his symptoms improved, laboratory results showed progressive correction of sodium (up to 132 mmol/L), normalization of bicarbonate to 23 mmol/L, resolution of ketonuria, and blood glucose stabilization at 7.5 mmol/L. At discharge, his treatment regimen included hydrocortisone (10 mg in the morning, 5 mg at noon, and 5 mg in the evening), levothyroxine 125 µg once daily, insulin therapy with insulin glargine (U-300), and insulin aspart.

Follow-up

Nivolumab therapy was permanently discontinued after 12 sessions. During follow-up, the patient remained under close oncological and endocrine surveillance. A positron emission tomography scan conducted 4 months after the last nivolumab administration demonstrated no fluorodeoxyglucose-avid recurrence at that time. In addition, a brain MRI performed approximately 7 months after the last nivolumab session showed no evidence of intracranial metastasis. The patient subsequently underwent several surgical procedures for melanoma recurrence (left arm and left and right thighs) and removal of basal cell carcinoma from the right ear as part of ongoing oncological management.

Endocrine follow-up included regular monitoring of thyroid function tests. Repeat evaluation of the corticotroph axis was not performed because assessment of cortisol concentrations is not reliable during glucocorticoid replacement therapy 3 times daily. Attempts to reduce the hydrocortisone dose resulted in recurrence of symptoms suggestive of hypocortisolemia. The patient has remained stable on antihypertensive therapy, levothyroxine (the dose was subsequently increased to 175 µg daily, based on TSH results), basal-bolus insulin, and hydrocortisone therapy.

DISCUSSION

Although ICI-induced hypophysitis is a well-described entity, this patient demonstrated isolated corticotroph deficiency without pituitary MRI abnormalities or additional pituitary hormone deficits. According to the diagnostic classifications proposed in 2023, this presentation is most consistent with ICI-associated isolated ACTH deficiency, rather than hypophysitis. However, ICI-related hypophysitis cannot be completely excluded, as MRI findings may be subtle or even normal,[14] and isolated corticotroph dysfunction may represent the only manifestation of pituitary inflammation.

This case illustrates the complexities in diagnosing and managing endocrinopathies associated with ICI, especially when preexisting autoimmune conditions (primary hypothyroidism and giant-cell arteritis) likely predisposed the patient to other autoimmune complications (eosinophilic asthma, diabetes, and adrenal insufficiency).

The severe headache experienced by the patient could have been due to mild hypophysitis (without radiological signs) or, more likely, due to hyponatremia, ketoacidosis, and secondary adrenal insufficiency, given the isolated deficiency of only one pituitary hormone. DKA, syndrome of inappropriate secretion of antidiuretic hormone and adrenal insufficiency, contributed to hyponatremia. Intravenous normal saline in conjunction with steroid therapy was effective to restore normal sodium concentration.

Early diagnosis of adrenal insufficiency remains challenging due to overlapping symptoms with malignancy and treatment side effects as illustrated in this case during nivolumab therapy. Baseline cortisol and ACTH concentrations can often remain within the normal range in early stages due to partial pituitary dysfunction.

Dynamic tests, such as the short Synacthen test, could be helpful, although they may be unreliable during the 1^st month of secondary adrenal insufficiency. ESE guidelines advise against delayed treatment and recommend considering glucocorticoid therapy in symptomatic patients with morning cortisol concentrations <360 nmol/L.[10]

High doses of corticosteroids, previously used to manage severe ICI-induced side effects, should be administered carefully in very specific cases, as literature suggests that they might reduce overall survival rates and interfere with the efficacy of the immunotherapy.[15]

The patient presented with DKA and poorly controlled DM despite insulin therapy, which may suggest progressive pancreatic β-cell dysfunction associated with nivolumab therapy. Patients undergoing ICI treatment who demonstrate hyperglycemia are at an increased risk of ICI-induced Type 1 diabetes. ICI-associated diabetes may present with heterogeneous phenotypes, which may require prompt insulin therapy, even if GAD autoantibodies are negative.[11] This condition is characterized by rapid onset, making early diagnosis and management crucial. Given the immunological effects of ICI therapy, clinicians should closely monitor blood glucose concentrations for early insulin therapy, regardless of antibody status.

A limitation of this report is the absence of repeat dynamic pituitary testing, which was not feasible due to ongoing glucocorticoid replacement therapy.

CONCLUSION

This case suggests that ICI therapy may be associated with severe multisystem endocrinopathies, including secondary adrenal insufficiency and insulin-dependent diabetes with ketoacidosis. Because early biochemical abnormalities may be subtle and symptoms may be nonspecific, clinicians must maintain a high index of suspicion and initiate prompt hormone replacement when adrenal insufficiency is suspected. Although endocrine irAEs are often manageable, severe presentations may require discontinuation of immunotherapy. Close multidisciplinary follow-up is essential, particularly in patients with preexisting autoimmune disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.