What are the management strategies for endocrinopathies (e.g. thyroid dysfunction, adrenal insufficiency, hyperglycemia) associated with immune-mediated immunotherapy?

Management of Endocrinopathies from Immune Checkpoint Inhibitor Therapy

Establish baseline endocrine function before starting immunotherapy and monitor systematically throughout treatment, with immediate hormone replacement for confirmed deficiencies—corticosteroids are NOT used to reverse endocrine damage but only for symptom control in select cases. 1

Baseline Screening and Monitoring Protocol

Before initiating any immune checkpoint inhibitor:

• Measure TSH, free T4, early morning ACTH and cortisol, glucose, and HbA1c 1
• Test for blood or urinary ketones if glucose elevation is noted 1

During treatment:

• Check TSH and free T4 before each cycle 1
• Obtain baseline metabolic panel each cycle to monitor glycemic trends 1
• Measure early morning ACTH and cortisol monthly for 6 months, then every 3 months for 6 months, then every 6 months for 1 year 1

Critical timing considerations:

• Median onset of endocrinopathies is 14.5 weeks (range 1.5-130 weeks) 1
• Hypophysitis typically occurs at 8-9 weeks with ipilimumab (after third dose) 1
• Insulin-dependent diabetes presents at median 20 weeks, with 59% presenting in ketoacidosis 1

Thyroid Dysfunction Management

Primary Hypothyroidism

Grade 1 (TSH >4.5 and <10 mIU/L, asymptomatic):

• Continue immunotherapy with TSH monitoring every 4-6 weeks 1

Grade 2 (TSH persistently >10 mIU/L, moderate symptoms):

• May continue or hold immunotherapy until symptoms resolve 1
• Initiate levothyroxine 1.6 mcg/kg/day (ideal body weight) 1
• Consider endocrine consultation for unusual presentations or difficulty titrating 1
• Titrate dose every 4-6 weeks based on TSH and free T4 1

Grade 3-4 (severe symptoms, unable to perform activities of daily living):

• Hold immunotherapy until symptoms resolve to baseline 1
• Start levothyroxine replacement immediately 1
• Endocrine consultation required 1

Thyroiditis with Hyperthyroidism

Grade 1 (asymptomatic or mild):

• Continue immunotherapy with close monitoring 1
• Check TSH and free T4 every 2-3 weeks to detect transition to hypothyroidism 1

Grade 2 (moderate symptoms):

• Consider holding immunotherapy until symptoms return to baseline 1
• Beta-blocker (atenolol or propranolol) for symptomatic relief 1
• Hydration and supportive care 1
• Corticosteroids are NOT routinely required and do not shorten duration 1
• For persistent hyperthyroidism >6 weeks, check TSI or TRAb and consider thionamide (methimazole or PTU) with endocrine referral 1

Grade 3-4 (severe symptoms or thyroid storm):

• Hold immunotherapy 1
• Hospitalize patient 1
• Initiate prednisone 1-2 mg/kg/day tapered over 1-2 weeks 1
• Consider SSKI or thionamide 1
• Endocrine consultation mandatory 1

Critical pitfall: Always measure BOTH TSH and free T4 in symptomatic patients—low TSH with low free T4 indicates central hypothyroidism from hypophysitis, not primary thyroid disease 1

Adrenal Insufficiency Management

Diagnostic Approach

Distinguish primary from secondary adrenal insufficiency:

• Primary: High ACTH with low morning cortisol, plus hyponatremia and hyperkalemia (though hyperkalemia present in only ~50% of cases) 1, 2
• Secondary: Low or inappropriately normal ACTH with low morning cortisol 1

Diagnostic thresholds:

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1, 2
• Morning cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion 1
• ACTH stimulation test: peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 1, 2

Treatment by Severity

Grade 1 (asymptomatic or mild):

• Consider holding immunotherapy until stabilized on replacement 1
• Endocrine consultation required 1
• Prednisone 5-10 mg daily OR hydrocortisone 10-20 mg every morning plus 5-10 mg early afternoon 1
• Add fludrocortisone 0.1 mg/day for primary adrenal insufficiency (mineralocorticoid replacement) 1

Grade 2 (moderate symptoms, able to perform activities of daily living):

• Consider holding immunotherapy until stabilized 1
• Endocrine consultation required 1
• Initiate stress-dose corticosteroids at 2-3 times maintenance: prednisone 20 mg daily OR hydrocortisone 20-30 mg morning plus 10-20 mg afternoon 1
• Taper to maintenance over 5-10 days 1

Grade 3-4 (severe symptoms, adrenal crisis):

• Hold immunotherapy until stabilized 1
• Endocrine consultation required 1
• NEVER delay treatment for diagnostic testing if adrenal crisis suspected 1, 2
• Immediate IV hydrocortisone 100 mg bolus 1, 2
• IV normal saline (at least 2 L initially) 1
• If diagnosis uncertain and you need to perform ACTH stimulation testing later, use dexamethasone 4 mg IV instead (does not interfere with cortisol assays) 2
• Taper stress-dose corticosteroids to maintenance over 4-6 weeks 1

Life-threatening pitfall: When treating patients with BOTH adrenal insufficiency and hypothyroidism, ALWAYS start corticosteroids several days BEFORE initiating thyroid hormone replacement—thyroid hormone increases cortisol metabolism and can precipitate adrenal crisis 1, 2, 3

Hypophysitis Management

Clinical presentation:

• Headache (85%) and fatigue (66%) are most common symptoms 1
• Visual changes are uncommon 1
• Low TSH with low free T4 suggests central etiology 1

• 75% have both central hypothyroidism and central adrenal insufficiency 1

• ~50% present with panhypopituitarism (adrenal insufficiency + hypothyroidism + hypogonadism) 1

Diagnostic workup:

• MRI of sella shows pituitary enlargement, stalk thickening, suprasellar convexity, heterogeneous enhancement 1
• MRI abnormalities typically resolve within 2 months 1

Treatment approach:

• Replace cortisol FIRST before thyroid hormone to prevent adrenal crisis 1
• Hydrocortisone 10-20 mg morning, 5-10 mg early afternoon 1
• After cortisol replacement established, add levothyroxine for central hypothyroidism 1
• Most cases result in permanent hormone deficiency requiring lifelong replacement 1

Incidence by agent:

• Ipilimumab 3 mg/kg: ≤10%; 10 mg/kg: up to 17% 1
• Combination ipilimumab/nivolumab: ≤13% 1
• PD-1 inhibitors alone: 0.4% 1
• PD-L1 inhibitors: <0.1% 1

Insulin-Dependent Diabetes Management

Clinical presentation:

• Polyuria, polydipsia, nausea, vomiting, abdominal pain, visual blurring 1
• 59% present with diabetic ketoacidosis 1
• 42% have evidence of pancreatitis 1
• 40% have positive autoantibodies 1
• 70% have concurrent immune-related adverse events 1

Diagnostic approach:

• Check glucose, HbA1c, blood or urinary ketones when glucose elevation noted 1
• Consider autoantibody testing (GAD65, IA-2, ZnT8) 1
• Assess for pancreatitis if clinically indicated 1

Management:

• Immediate insulin therapy required—this is insulin-DEPENDENT diabetes 1
• Treat diabetic ketoacidosis per standard protocols if present 1
• Endocrine consultation for insulin regimen optimization 1
• Corticosteroids do NOT reverse beta cell destruction 1
• Immunotherapy may be continued with careful glucose monitoring 1

Key Principles Across All Endocrinopathies

Corticosteroid use:

• High-dose corticosteroids do NOT mitigate permanent organ damage in immune checkpoint inhibitor-related endocrinopathies 1
• Most endocrinopathies require lifelong hormone replacement 1
• Corticosteroids are used for symptom control in severe cases, NOT to preserve endocrine function 1

Patient education essentials:

• All patients need education on stress dosing for adrenal insufficiency 1, 2
• Medical alert bracelet required for adrenal insufficiency 1, 2
• Endocrine consultation before surgery or procedures for stress-dose planning 2

Immunotherapy continuation:

• Thyroid dysfunction and diabetes typically allow continuation of immunotherapy with appropriate hormone replacement 1
• Adrenal insufficiency requires holding therapy until stabilized on replacement 1
• Severe endocrinopathies (Grade 3-4) require permanent discontinuation in some cases 1

Endocrinology referral indications:

• All cases of hypophysitis 1
• Severe or complex endocrinopathies 1
• Difficulty titrating hormone therapy 1
• Primary adrenal insufficiency 1
• New-onset insulin-dependent diabetes 1