Introduction: The Rising Challenge of Immunotherapy-Induced Endocrinopathies

Immune checkpoint inhibitors (ICIs) have fundamentally transformed the landscape of modern oncology, offering durable responses across various malignancies. However, these therapies frequently trigger immune-related adverse events (irAEs) that can affect virtually any organ system. Among these, endocrine toxicities are particularly prevalent and can often present with vague, non-specific symptoms. Toripalimab-induced ACTH deficiency is a rare but clinically significant condition that physicians must remain vigilant for during treatment. Unlike the more generalized hypophysitis often seen with CTLA-4 inhibitors, PD-1 inhibitors like toripalimab typically cause an isolated loss of the adrenocorticotropic hormone. Because the clinical presentation often mimics general malaise or gastrointestinal distress, these cases frequently go undiagnosed for extended periods. This specific case report describes a patient with cholangiocarcinoma who suffered for two years with symptoms mistakenly attributed to drug toxicity. The delay in diagnosis highlights the critical need for a high index of suspicion. Early recognition is vital, as secondary adrenal insufficiency can be life-threatening if left untreated. Understanding the unique presentation of toripalimab-induced ACTH deficiency is essential for clinicians managing patients on these novel immunotherapies.

Clinical Presentation: When Gastroparesis Masks Isolated ACTH Deficiency

The patient in this report experienced a complex diagnostic journey characterized by persistent gastrointestinal symptoms and precordial discomfort. For nearly two years, the recurrent nausea and delayed gastric emptying were attributed to either the primary malignancy or the side effects of lenvatinib. This phenomenon is known as diagnostic anchoring, where clinicians fixate on initial assumptions rather than considering new etiologies. Consequently, the patient underwent surgery, yet the symptoms of refractory delayed gastric emptying persisted postoperatively. Interestingly, the patient did not exhibit the classic "adrenal crisis" symptoms of severe hypotension or electrolyte collapse initially. Instead, the manifestation of toripalimab-induced ACTH deficiency as gastroparesis highlights the atypical ways adrenal insufficiency can surface. Cortisol plays a vital role in maintaining normal gastric motility and mucosal integrity. When cortisol levels drop due to isolated ACTH deficiency, the digestive process can slow significantly, mimicking functional gastrointestinal disorders. Doctors should therefore consider endocrine testing in any ICI-treated patient with unexplained, persistent abdominal complaints. Recognizing these subtle signs can prevent unnecessary surgical interventions and lead to more effective therapy.

Mechanism of Action: Why Toripalimab Spares Other Pituitary Axes

To understand toripalimab-induced ACTH deficiency, one must look at the specific immunobiology of PD-1 inhibitors compared to other checkpoint classes. Anti-CTLA-4 antibodies often cause a diffuse inflammatory hypophysitis that affects multiple pituitary hormone axes and shows clear enlargement on MRI. Conversely, PD-1 and PD-L1 inhibitors like toripalimab are much more likely to cause isolated ACTH deficiency (IAD). In these cases, the thyroid-stimulating hormone (TSH), growth hormone, and gonadotropins typically remain entirely functional. Furthermore, imaging studies such as pituitary MRIs are often completely normal in over 80% of patients with PD-1-induced IAD. This lack of structural change makes the diagnosis even more difficult for the unwary clinician. Researchers suggest that the mechanism may involve specific T-cell-mediated destruction of corticotroph cells or subclinical inflammation that does not cause visible edema. Because the mineralocorticoid axis remains intact—since aldosterone is regulated by the renin-angiotensin system rather than ACTH—these patients rarely present with the hyperkalemia typical of primary adrenal failure. This biochemical nuance often leads to the misinterpretation of mild hyponatremia as simple dehydration or syndrome of inappropriate antidiuretic hormone secretion (SIADH).

The Diagnostic Journey: Avoiding Anchor Bias in Oncology

One of the most significant hurdles in identifying toripalimab-induced ACTH deficiency is the presence of overlapping symptoms from other therapies. In this case, the patient was also receiving lenvatinib, a multi-kinase inhibitor notorious for causing fatigue, nausea, and hypertension. When a patient presents with multiple somatic complaints, it is tempting for the medical team to attribute everything to the known side-effect profile of the current drugs. This case serves as a powerful reminder to look beyond the obvious. Diagnostic workup for IAD requires a focused laboratory assessment, starting with morning serum cortisol and ACTH levels. A low morning cortisol level coupled with a low or inappropriately normal ACTH level points directly toward secondary adrenal insufficiency. In many instances, the diagnosis is only confirmed when dynamic testing, such as the ACTH stimulation test, is performed. Furthermore, clinicians must differentiate between primary and secondary adrenal insufficiency to guide proper management. While the patient’s symptoms were mistakenly attributed to drug toxicity for two years, the eventual discovery of IAD led to a rapid clinical turnaround. Avoiding anchor bias requires a systematic approach to every new or worsening symptom in the oncology setting.

Management Strategies and Glucocorticoid Replacement

Once the diagnosis of toripalimab-induced ACTH deficiency is established, the cornerstone of management is physiological glucocorticoid replacement. Unlike many other immune-related adverse events, IAD is usually permanent, meaning the patient will likely require lifelong hormone therapy. Hydrocortisone is the preferred agent due to its short half-life, allowing for a dosing schedule that mimics the natural circadian rhythm of cortisol. Alternatively, prednisone can be used for its once-daily convenience. In the case presented, the initiation of glucocorticoid replacement resulted in the rapid resolution of both the precordial discomfort and the gastroparesis. This dramatic improvement confirms that the symptoms were directly related to the hormonal deficit rather than structural gastric disease. Patients must also be educated on "stress dosing" for periods of illness or surgery to prevent a catastrophic adrenal crisis. Although the oncology team may be tempted to permanent discontinue the ICI, many guidelines suggest that toripalimab can be resumed once the patient is stable on replacement therapy. Successful management relies on close collaboration between oncologists and endocrinologists to ensure the patient remains safe while continuing their life-prolonging cancer treatment.

Clinical Pearls for the Indian Medical Context

In India, where the use of ICIs like toripalimab is increasing in tertiary care centers, clinicians must adapt to these complex toxicities. Financial constraints and distance to specialized centers often mean that patients may present with advanced symptoms before being evaluated. Therefore, Indian physicians should emphasize patient education regarding the red flags of adrenal insufficiency, such as profound fatigue or unexplained nausea. Additionally, when managing patients with chronic GI symptoms, the possibility of an underlying endocrine trigger should be evaluated before embarking on expensive gastrointestinal procedures. Screening with a simple morning cortisol test is a cost-effective first step in the Indian healthcare setting. Given the high prevalence of tuberculosis and other infections in India, clinicians must also be careful to rule out infectious causes of adrenal dysfunction. However, in the context of active immunotherapy, an immune-related etiology should always be at the top of the differential list. By fostering a multidisciplinary approach involving oncology, gastroenterology, and endocrinology, we can improve outcomes and quality of life for our patients. This case illustrates that even the most refractory gastrointestinal symptoms can sometimes have a straightforward hormonal solution.

Frequently Asked Questions

How does toripalimab-induced ACTH deficiency differ from classic hypophysitis?

Toripalimab-induced ACTH deficiency is typically an isolated hormonal loss, whereas classic hypophysitis, often seen with CTLA-4 inhibitors, affects multiple pituitary hormones like TSH and FSH. In isolated ACTH deficiency, the pituitary gland usually appears normal on MRI scans, making it harder to detect visually. Conversely, classic hypophysitis often presents with visible pituitary enlargement and more global symptoms of hormone failure, requiring more complex replacement strategies beyond just glucocorticoids.

Why does adrenal insufficiency sometimes present as gastroparesis?

Cortisol is essential for maintaining the normal function of the autonomic nervous system and the gastrointestinal tract. A deficiency in cortisol can lead to impaired gastric smooth muscle contraction and delayed emptying, clinically manifesting as gastroparesis. When toripalimab-induced ACTH deficiency occurs, the lack of cortisol disrupts these metabolic and motor pathways. Patients then experience refractory nausea and vomiting, which often resolve quickly once physiologic glucocorticoid replacement therapy is initiated and hormone levels stabilize.

Is it safe to continue toripalimab after a diagnosis of isolated ACTH deficiency?

Yes, most clinical guidelines suggest that toripalimab and other immune checkpoint inhibitors can be continued once the patient is stable on glucocorticoid replacement. Unlike other severe immune-related adverse events like pneumonitis or colitis, isolated ACTH deficiency is manageable with lifelong hormone therapy and does not usually require permanent discontinuation of the immunotherapy. However, the patient must be closely monitored by an endocrinologist and educated on the necessity of stress-dosing during times of physical illness.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or establish a doctor-patient relationship. Always seek the advice of a qualified healthcare provider regarding any medical condition or treatment. Refer to the latest local and national guidelines for clinical practice.

References

Lu C et al. Toripalimab-induced isolated ACTH deficiency associated with gastroparesis: a case report. J Med Case Rep. 2026 Jul 18. doi: 10.1186/s13256-026-06375-3. PMID: 42471731.

Higham CE et al. Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline. Eur J Endocrinol. 2022;187(6):G1-G21.

Schneider HJ et al. Isolated ACTH deficiency: an underdiagnosed cause of secondary adrenal insufficiency. Clin Endocrinol (Oxf). 2021;95(6):790-801.