Endocrine

Immune checkpoint inhibitor endocrinopathies

Clinical Overview and When to Suspect ICI Endocrinopathies

— Anti-CTLA-4: hypophysitis (up to 10–17% with ipilimumab, especially at higher doses), less thyroid disease

— Anti-PD-1/PD-L1: thyroid dysfunction predominates (10–20%); hypophysitis rare (<1%)

— Combination ipilimumab + nivolumab: highest overall risk; hypophysitis up to 8–13%, thyroiditis up to 20%

— Thyroid dysfunction (thyroiditis → transient hyperthyroidism → hypothyroidism)

— Hypophysitis with secondary adrenal insufficiency, central hypothyroidism, hypogonadism

— Primary adrenal insufficiency (rare, <1%)

— Insulin-deficient (type 1–like) diabetes mellitus, often presenting in DKA

— Hypoparathyroidism (rare)

Board pearl: A patient on pembrolizumab presenting with fatigue and hyponatremia must be evaluated for both thyroid dysfunction and adrenal insufficiency — replacing thyroid hormone before glucocorticoids in coexisting adrenal insufficiency can precipitate adrenal crisis.

Immune checkpoint inhibitors (ICIs) — monoclonal antibodies blocking CTLA-4 (ipilimumab), PD-1 (nivolumab, pembrolizumab, cemiplimab), or PD-L1 (atezolizumab, durvalumab, avelumab) — unleash T-cell activity against tumors but commonly trigger immune-related adverse events (irAEs), with endocrine glands disproportionately affected.

Endocrine irAEs are among the most common and often permanent toxicities; unlike colitis or pneumonitis, they usually do not require ICI discontinuation because hormone replacement is straightforward.

Frequency by drug class:

Major endocrine syndromes to recognize:

When to suspect: any cancer patient on ICI presenting with fatigue, headache, nausea, weight change, polyuria, hypotension, or vague malaise — check TSH, free T4, AM cortisol, glucose, electrolytes, and ACTH.

Onset: thyroiditis typically within 6 weeks; hypophysitis 6–12 weeks; T1DM variable, often after months; adrenal insufficiency anytime.

Presentation Patterns and Key History

— Transient thyrotoxic phase weeks 2–6: palpitations, heat intolerance, tremor, weight loss, anxiety; often asymptomatic and detected on labs

— Followed by hypothyroid phase weeks 6–12: fatigue, cold intolerance, constipation, dry skin, weight gain, depression — frequently permanent

— Headache (often the earliest clue), fatigue, nausea, anorexia, dizziness, low libido, sometimes visual field changes (rare; less mass effect than lymphocytic hypophysitis)

— Symptoms of secondary adrenal insufficiency: orthostasis, hyponatremia, hypoglycemia

— Diabetes insipidus is uncommon with ICI hypophysitis (unlike lymphocytic hypophysitis)

— Fatigue, weight loss, hyperpigmentation, salt craving, hypotension, hyperkalemia + hyponatremia

— Abrupt polyuria, polydipsia, weight loss; up to 70% present in DKA

— Median onset ~6–9 weeks but ranges widely; HbA1c often only modestly elevated reflecting rapid β-cell destruction

— Specific ICI agent, dose number, time since last infusion

— Prior autoimmune disease (psoriasis, vitiligo, Hashimoto's) — increases irAE risk

— Concurrent steroids, opioids, or megestrol (can mask or mimic)

— Family history of autoimmune endocrinopathy

— Prior pituitary radiation or brain metastases (alters differential)

Key distinction: Thyroiditis classically follows a biphasic course (hyperthyroid → hypothyroid) with low radioactive iodine uptake and suppressed TSH initially, while central hypothyroidism from hypophysitis shows low or inappropriately normal TSH with low free T4 plus other anterior pituitary deficits — never just check TSH alone in an ICI patient.

Thyroiditis pattern (most common, PD-1/PD-L1):

Hypophysitis (CTLA-4 > combination > PD-1):

Primary adrenal insufficiency:

ICI-induced diabetes:

Hypoparathyroidism: paresthesias, carpopedal spasm, tetany, seizures

Key history elements to elicit:

Physical Exam Findings and Hemodynamic Assessment

— Hypotension, orthostasis, tachycardia: red flags for adrenal insufficiency or adrenal crisis

— Fever with hypotension in an ICI patient = consider adrenal crisis even before sepsis is confirmed

— Weight changes documented across visits help track thyroid trajectory

— Warm moist skin, fine tremor, lid lag, tachycardia, hyperreflexia

— Goiter usually absent (silent/destructive thyroiditis) — distinguishes from Graves

— No exophthalmos or pretibial myxedema

— Bradycardia, dry coarse skin, delayed relaxation phase of deep tendon reflexes, periorbital edema, hoarse voice

— Severe cases: hypothermia, altered mentation → myxedema coma

— Often unremarkable except postural changes

— Visual field testing (confrontation) — bitemporal hemianopsia rare but check

— Cranial nerves III, IV, VI if cavernous sinus involvement suspected

— Primary: hyperpigmentation of palmar creases, buccal mucosa, scars (high ACTH)

— Secondary (hypophysitis): no hyperpigmentation, pale skin, decreased axillary/pubic hair

— Signs of dehydration, Kussmaul respirations, fruity breath, altered mentation if DKA

— Chvostek sign (facial twitch on tapping facial nerve), Trousseau sign (carpal spasm with BP cuff inflation)

Step 3 management: Any ICI patient with SBP <90, AMS, or unexplained hypoglycemia — draw cortisol/ACTH and empirically give hydrocortisone 100 mg IV before confirmatory results. Document orthostatic vitals (lying then standing after 3 min) at every visit while on ICI; a drop ≥20 mmHg SBP warrants adrenal axis testing.

General/vital signs assessment — the cornerstone in ICI patients:

Thyrotoxic phase exam:

Hypothyroid phase exam:

Hypophysitis exam:

Adrenal insufficiency exam:

ICI-T1DM exam:

Hypoparathyroidism:

Diagnostic Workup — Initial Labs and Imaging

— TSH and free T4

— Basic metabolic panel including glucose, sodium, potassium

— Consider AM cortisol periodically, especially before cycles 3–4 when hypophysitis peaks

— TSH, free T4, free T3

— 8 AM cortisol and ACTH (drawn together, before any steroid dose)

— Sodium, potassium, glucose, BUN/creatinine

— LH, FSH, total testosterone (men) or estradiol (women), prolactin, IGF-1

— HbA1c, β-hydroxybutyrate, anion gap, venous pH if hyperglycemia

— Calcium, phosphorus, PTH, magnesium if paresthesias

— Suppressed TSH + elevated free T4/T3 → thyrotoxicosis (thyroiditis vs. Graves)

— Elevated TSH + low free T4 → primary hypothyroidism

— Low or inappropriately normal TSH + low free T4 → central hypothyroidism (hypophysitis)

— AM cortisol <3 μg/dL → adrenal insufficiency confirmed

— AM cortisol >18 μg/dL → adrenal insufficiency excluded

— Indeterminate 3–18 → cosyntropin stimulation test

— High ACTH + low cortisol → primary; low/inappropriately normal ACTH + low cortisol → secondary (central)

— Diffuse pituitary enlargement, stalk thickening, heterogeneous enhancement

— MRI may be normal in 25% — do not exclude hypophysitis on imaging alone

Board pearl: Always draw cortisol and ACTH before giving steroids — if the patient is hemodynamically unstable, draw, then treat. A single suppressed TSH in an ICI patient does not distinguish thyroiditis from Graves — free T4, T3, and clinical context do.

Baseline labs before each ICI cycle (standard of care):

When endocrine irAE suspected, order simultaneously:

Interpreting thyroid labs:

Interpreting cortisol/ACTH:

Imaging — pituitary MRI with contrast if hypophysitis suspected:

ECG: check QTc if hypocalcemia or severe hypothyroidism

Diagnostic Workup — Advanced and Confirmatory Studies

— 250 μg cosyntropin IV/IM; measure cortisol at 30 and 60 min

— Peak cortisol <18 μg/dL → adrenal insufficiency

— Caveat: in acute secondary AI (<4–6 weeks), adrenals not yet atrophied, so stim test may be falsely normal — rely on AM cortisol + ACTH and clinical picture

— Radioactive iodine uptake (RAIU) scan: low uptake in destructive thyroiditis; diffusely elevated in Graves

— TSI/TRAb: positive in Graves, negative in ICI thyroiditis

— Thyroid ultrasound: hypoechoic, decreased vascularity in thyroiditis

— Anti-TPO/anti-Tg antibodies often positive in ICI thyroiditis but not required for diagnosis

— Free T4, AM cortisol/ACTH, LH/FSH/testosterone or estradiol, prolactin (may be low or mildly elevated), IGF-1

— Posterior pituitary: serum/urine osmolality, sodium — DI rare but check if polyuric

— Low/undetectable C-peptide despite hyperglycemia → insulinopenia

— GAD-65, IA-2, ZnT8, islet cell antibodies — positive in ~40–50%; absence does not exclude

— Distinguish from steroid-induced hyperglycemia (preserved C-peptide, no ketosis)

— Low calcium + low/inappropriately normal PTH + normal magnesium → autoimmune hypoparathyroidism

— Activating CaSR autoantibodies (research, not routine)

Key distinction: In ICI thyroiditis vs. Graves disease, the RAIU scan is the gold standard differentiator — low uptake in thyroiditis means antithyroid drugs (methimazole, PTU) are useless and inappropriate; only β-blockers are indicated for symptom control.

Cosyntropin (ACTH) stimulation test for adrenal insufficiency:

Thyroid differentiation when thyrotoxic:

Pituitary workup — full anterior axis:

ICI-induced diabetes confirmation:

Hypoparathyroidism workup:

Visual field testing (formal perimetry) if hypophysitis with mass effect concern

Risk Stratification and First-Line Management Logic

— Grade 1: asymptomatic/mild — continue ICI, treat with replacement

— Grade 2: moderate symptoms — usually continue ICI, treat

— Grade 3–4: severe/life-threatening — hold ICI, hospitalize, high-dose steroids if inflammatory (hypophysitis), replacement therapy

— Unlike colitis, pneumonitis, hepatitis — high-dose immunosuppression rarely reverses gland destruction

— Goal is hormone replacement, not anti-inflammatory therapy, except in hypophysitis with mass effect/visual symptoms or symptomatic severe inflammation

— ICI can usually be continued once patient is stable on replacement

— Thyroiditis hyperthyroid phase → β-blocker (propranolol/atenolol); no methimazole

— Hypothyroidism → levothyroxine

— Hypophysitis → hydrocortisone first, then levothyroxine; high-dose steroids only if mass effect or grade 3–4 inflammatory symptoms

— Primary AI → hydrocortisone + fludrocortisone

— T1DM → insulin (basal-bolus), DKA protocol if applicable

— Hypoparathyroidism → calcium + calcitriol

— Adrenal crisis, DKA, myxedema coma, hypophysitis with visual compromise, severe hypocalcemia with tetany/seizure

— Resume once hemodynamically stable and replacement therapy established

Step 3 management: Sequence matters — always replace cortisol before thyroid hormone in suspected combined deficiency. Thyroid hormone increases cortisol metabolism and can precipitate adrenal crisis in untreated AI. Confirm adrenal axis is intact (or treated) before initiating levothyroxine in any ICI patient with central hypothyroidism.

CTCAE grading guides management (analogous across endocrinopathies):

Core management principle unique to endocrine irAEs:

Decision tree:

When to hold the ICI:

Pharmacotherapy — First-Line Replacement Regimens

— Young, healthy: full replacement 1.6 μg/kg/day PO once daily, empty stomach

— Elderly or CAD: start 25–50 μg/day, titrate every 6 weeks

— Goal TSH 0.5–4.5 mIU/L for primary hypothyroidism

— Central hypothyroidism (hypophysitis): titrate by free T4, not TSH (TSH unreliable); target free T4 in upper half of normal range

— Propranolol 10–40 mg PO q6–8h or atenolol 25–50 mg daily

— Continue until free T4 normalizes (typically 4–8 weeks); no antithyroid drugs needed

— Hydrocortisone 15–25 mg/day divided (e.g., 10 mg AM, 5 mg early afternoon, 2.5 mg late afternoon)

— Alternative: prednisone 3–5 mg daily

— Mineralocorticoid (primary AI only): fludrocortisone 0.05–0.2 mg daily; titrate by BP, K, renin

— Stress dosing: double or triple oral dose for febrile illness; IV hydrocortisone 100 mg for surgery, trauma, or vomiting

— Hypophysitis with severe headache, visual changes, or mass effect: prednisone 1–2 mg/kg/day or methylprednisolone 1 mg/kg IV, taper over 2–4 weeks

— Severe thyrotoxicosis (rare thyroid storm picture)

— Basal-bolus regimen: glargine/detemir + rapid-acting (lispro/aspart) at meals

— Total daily dose ~0.5 units/kg/day, 50% basal / 50% prandial

— DKA: IV insulin infusion, IV fluids, K replacement per protocol

— Calcium carbonate 1–2 g elemental BID–TID + calcitriol 0.25–0.5 μg BID

Board pearl: A MedicAlert bracelet and a hydrocortisone injection kit (Solu-Cortef 100 mg) for home use are mandatory discharge items for any patient with new adrenal insufficiency from hypophysitis.

Levothyroxine for hypothyroidism:

β-blockers for thyrotoxic phase:

Glucocorticoid replacement (chronic AI, primary or secondary):

High-dose steroids — when actually indicated in endocrine irAEs:

Insulin for ICI-T1DM:

Calcium/calcitriol for hypoparathyroidism:

Advanced Pharmacology and ICI Rechallenge Decisions

— Endocrinopathies are not a contraindication to continued ICI therapy once replacement is established and patient stable

— In contrast to grade 3–4 colitis/pneumonitis/hepatitis where permanent discontinuation often required

— Hypophysitis: resume ICI once on stable glucocorticoid + thyroid replacement; no need for prolonged immunosuppressive taper before resumption

— T1DM: resume once glucose controlled on insulin and DKA resolved

— High-dose prednisone 1–2 mg/kg/day × 1–2 weeks

— Taper over 4–6 weeks down to physiologic replacement dose (hydrocortisone 15–25 mg/day or prednisone 5 mg) — do not stop, as pituitary-adrenal axis usually permanently damaged

— Repeat MRI in 4–6 weeks to confirm resolution of pituitary enlargement

— Levothyroxine absorption reduced by calcium, iron, PPIs, sucralfate, bile acid sequestrants — separate by 4 hours

— Phenytoin, rifampin, carbamazepine increase levothyroxine clearance — may need dose increase

— Hydrocortisone clearance increased by enzyme inducers

— Concurrent immunotherapy + targeted therapy (e.g., ICI + BRAF/MEK): cumulative endocrine toxicity, more frequent monitoring

— Stress dose steroids for procedures: minor (dental) — no change; moderate (colonoscopy with sedation) — 50 mg hydrocortisone; major surgery — 100 mg IV q8h on day of surgery, taper over 48–72 h

— Severe thyrotoxicosis with cardiac symptoms: consider cholestyramine to bind thyroid hormone

— DDAVP only if true central DI documented (rare)

Step 3 management: Counsel every patient with new AI: "sick day rules" — for fever ≥38°C, vomiting, or significant illness, double or triple oral hydrocortisone; for inability to tolerate PO, administer IM Solu-Cortef 100 mg and call ED.

ICI rechallenge after endocrine irAE:

Steroid taper logistics in hypophysitis with mass effect:

Drug interactions to watch:

Special pharmacologic situations:

Symptomatic adjuncts:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher baseline cardiovascular comorbidity → start levothyroxine at 25–50 μg/day, titrate every 6–8 weeks

— Overreplacement risk: atrial fibrillation, osteoporosis, falls

— Subtle presentation of adrenal crisis — may present as isolated confusion, hypotension, or "failure to thrive" without classic features

— Polypharmacy interactions with levothyroxine absorption (omeprazole, calcium, iron)

— Cosyntropin stim test reliable; AM cortisol thresholds unchanged

— Levothyroxine dosing unchanged (not renally cleared)

— Hydrocortisone unchanged

— Fludrocortisone: monitor potassium closely; may need dose reduction if hyperkalemia

— Insulin dosing: reduce by 25–50% if CrCl <30 (decreased clearance, hypoglycemia risk)

— Metformin contraindicated if eGFR <30; not first-line for ICI-T1DM anyway (insulin needed)

— Contrast for pituitary MRI: gadolinium avoided if eGFR <30 (NSF risk) — use noncontrast if needed

— Hydrocortisone activation unaffected (already active); prednisone requires hepatic conversion to prednisolone — prefer hydrocortisone in severe liver disease

— Levothyroxine metabolism altered; monitor free T4 more frequently

— β-blockers: prefer atenolol (renally cleared) over propranolol (hepatic) in liver disease

— ECOG 3–4 patients: balance hormone replacement benefit against goals of care

— Hospice transitions: continue physiologic glucocorticoid replacement — abrupt withdrawal causes crisis even in dying patients

Board pearl: An 80-year-old on pembrolizumab admitted for "altered mental status and hypotension" with sodium 128 — draw AM cortisol and TSH/free T4 before attributing to UTI or dehydration; ICI hypophysitis is the diagnosis until proven otherwise.

Elderly considerations:

Renal impairment:

Hepatic impairment:

Performance status considerations:

Special Populations — Pregnancy, Pediatrics, and Survivors

— ICI use during pregnancy is generally avoided (potential teratogenicity, fetal immune dysregulation via placental transfer of IgG)

— If endocrine irAE develops in a patient who becomes pregnant on ICI:

— Levothyroxine: safe; increase dose by ~30% during pregnancy; target TSH per trimester (1st: <2.5; 2nd–3rd: <3.0)

— Hydrocortisone: safe (does not cross placenta in active form due to placental 11β-HSD2); prednisolone preferred over dexamethasone (crosses placenta)

— Insulin: safe and preferred for diabetes management

— Stress-dose steroids during labor and delivery mandatory in adrenal insufficiency

— ICIs approved in select pediatric malignancies (Hodgkin lymphoma, melanoma, MSI-high tumors)

— Endocrine irAE patterns similar; thyroid dysfunction most common

— Levothyroxine dosing weight-based: infants 10–15 μg/kg/day; older children 4–6 μg/kg/day

— Growth and pubertal monitoring critical — hypophysitis can cause growth hormone and gonadotropin deficiency with long-term developmental implications

— Endocrinopathies are usually permanent; lifelong replacement needed

— Annual screening DEXA after 5 years of glucocorticoid replacement

— Cardiovascular risk modification (statins, BP control) — increased CV mortality in chronic adrenal insufficiency

— Fertility counseling for young patients with hypophysitis (hypogonadism → infertility) — refer to reproductive endocrinology

Step 3 management: For a pregnant patient with prior ICI-induced hypophysitis, increase levothyroxine by 30% as soon as pregnancy confirmed, recheck TSH/free T4 every 4 weeks, and ensure stress-dose IV hydrocortisone is documented in the delivery plan and on the L&D order set.

Pregnancy:

Pediatrics:

Cancer survivors / long-term follow-up:

Complications and Adverse Outcomes

— Triggered by missed doses, infection, surgery, GI illness

— Hypotension refractory to fluids, hypoglycemia, hyponatremia, hyperkalemia (primary AI), shock, death

— Mortality up to 6% per crisis episode; preventable with patient education + emergency kit

— Severe untreated hypothyroidism: hypothermia, bradycardia, hyponatremia, hypercapnia, altered mentation

— Treatment: IV levothyroxine ± T3, IV hydrocortisone (until AI excluded), supportive care

— Mortality 30–50%

— Up to 70% of ICI-T1DM presents in DKA — high mortality if delayed recognition

— Cerebral edema risk in pediatrics with rapid correction

— Rare in ICI thyroiditis (self-limited destructive process); more concerning in unrecognized concurrent Graves

— Permanent panhypopituitarism in majority

— Visual field defects (rare, usually transient with steroids)

— Hyponatremia from cortisol deficiency (SIADH-like picture)

— Osteoporosis from chronic glucocorticoids (even physiologic doses) — DEXA monitoring

— Atrial fibrillation, bone loss from overreplaced levothyroxine

— Insulin-induced hypoglycemia, weight gain

— Fatigue, depression, sexual dysfunction common — under-recognized

— Chronic replacement burden affects medication adherence

— Development of endocrine irAE is associated with improved tumor response in melanoma and lung cancer — counsel patients that the toxicity may herald efficacy

Key distinction: Adrenal crisis in primary AI presents with hyperkalemia and hyperpigmentation; secondary AI from hypophysitis presents with normal-to-low potassium (mineralocorticoid intact) and no hyperpigmentation — both still need urgent IV hydrocortisone 100 mg.

Adrenal crisis — most feared:

Myxedema coma:

Diabetic ketoacidosis:

Thyroid storm:

Hypophysitis-related complications:

Long-term complications of replacement therapy:

Quality-of-life impact:

Cancer outcomes:

When to Escalate Care — ICU, Consult, Inpatient Triage

— Suspected adrenal crisis (hypotension, AMS, hypoglycemia, electrolyte derangement)

— DKA from new-onset ICI-T1DM

— Myxedema coma

— Hypophysitis with visual changes or severe headache

— Symptomatic hypocalcemia (tetany, seizure, prolonged QT)

— Severe thyrotoxicosis with cardiac decompensation

— Hemodynamic instability requiring vasopressors

— DKA with pH <7.0, altered mentation, or hemodynamic instability

— Myxedema coma (close monitoring, mechanical ventilation often needed)

— Adrenal crisis with shock not responding to initial hydrocortisone + fluids

— Severe hyponatremia (<120) with neurologic symptoms

— Any new ICI endocrinopathy — strongly recommended

— Hypophysitis (panhypopituitarism workup, replacement strategy)

— Diagnostic ambiguity (e.g., thyroiditis vs. Graves)

— Adrenal crisis management and follow-up

— Pregnancy in ICI patient

— Visual changes in hypophysitis

— Decision to hold vs. continue ICI — joint decision with oncology

— Communicate replacement plan and stress-dose protocol

— Stat: glucose, BMP, AM cortisol, ACTH, TSH, free T4, ABG/VBG if DKA, ECG

— Empiric hydrocortisone 100 mg IV if crisis suspected (after labs drawn)

— IV fluids: NS for volume; D5NS if hypoglycemic

— Pituitary MRI when stable

— Endocrinology consult

— Hold ICI pending stabilization

CCS pearl: For a patient on combo ipi/nivo presenting with hypotension and Na 124, sequence orders as: (1) draw cortisol, ACTH, TSH, free T4, BMP, glucose; (2) IV hydrocortisone 100 mg; (3) NS bolus; (4) admit; (5) endocrine consult; (6) pituitary MRI when stable — do not delay steroids waiting for confirmatory testing.

Immediate ED/inpatient admission:

ICU criteria:

Endocrinology consultation indications:

Ophthalmology consult:

Oncology coordination:

Inpatient workup checklist (CCS-style):

Key Differentials — Same-Category (Endocrine) Causes

— Both: suppressed TSH, elevated free T4/T3

— Graves: diffuse uptake on RAIU, positive TRAb/TSI, ophthalmopathy, pretibial myxedema, persistent (not biphasic)

— ICI thyroiditis: low RAIU, negative TRAb, biphasic course, no eye signs

— De Quervain's: painful, tender thyroid, post-viral, elevated ESR/CRP, fever

— ICI thyroiditis: painless, no preceding viral illness, lab inflammation absent

— Both can have positive anti-TPO; ICI accelerates underlying autoimmunity in predisposed patients

— Clinically managed identically with levothyroxine

— Primary: high ACTH, hyperkalemia, hyperpigmentation, salt craving

— Secondary (hypophysitis): low/normal ACTH, normokalemia, no hyperpigmentation, other anterior pituitary deficits

— Metastasis: discrete mass, often with DI (posterior pituitary involvement more common), older age, history of breast/lung primary

— Hypophysitis: diffuse enlargement, stalk thickening, anterior dysfunction predominant

— ICI-T1DM: low C-peptide, ketosis, often DKA, may have autoantibodies

— Steroid-induced: preserved C-peptide, no ketosis, postprandial predominant

— ICI can cause both — check lipase, imaging; pancreatitis typically has abdominal pain

— Check magnesium first — repletion may correct PTH

Key distinction: A thyrotoxic ICI patient with goiter, eye involvement, or persistent (non-biphasic) hyperthyroidism needs TRAb and RAIU to exclude Graves before declaring ICI thyroiditis — treatment differs (antithyroid drugs for Graves, β-blockers alone for thyroiditis).

Differentiating ICI thyroiditis from Graves disease:

Differentiating ICI thyroiditis from subacute (de Quervain's):

Hashimoto's vs. ICI hypothyroidism:

Primary vs. secondary adrenal insufficiency:

Hypophysitis vs. pituitary metastasis:

ICI-T1DM vs. steroid-induced hyperglycemia:

ICI-T1DM vs. pancreatic insufficiency from pancreatitis:

Autoimmune hypoparathyroidism vs. hypomagnesemia-induced:

Key Differentials — Other-Category Causes

— Both present similarly; treat as both — broad-spectrum antibiotics + IV hydrocortisone, draw cortisol/ACTH/cultures first

— Hypoglycemia and eosinophilia favor AI; lactic acidosis can occur in both

— Always consider tumor progression; staging imaging if uncertain

— Endocrinopathy more likely if hyponatremia, hypoglycemia, or specific hormonal symptoms

— MRI distinguishes; brain mets typically multifocal, leptomeningeal

— Hypophysitis confined to sella with stalk involvement

— SIADH (small cell lung cancer) vs. cortisol deficiency hyponatremia — check cortisol

— Ectopic ACTH → Cushing's, not AI; opposite picture

— Hepatitis (fatigue, nausea) — check LFTs

— Colitis with electrolyte loss — diarrhea history

— Myocarditis — troponin, ECG; can co-occur with endocrinopathy

— Nephritis with hyponatremia — check urinalysis, creatinine

— Opioid-induced hypogonadism and adrenal suppression

— Megestrol acetate (used for cachexia) causes secondary AI

— Chemotherapy-induced hypothyroidism (less commonly, e.g., TKIs like sunitinib)

— Glucocorticoids given for other irAEs → iatrogenic AI on withdrawal

— Tuberculosis adrenalitis in immunocompromised

— CMV adrenalitis

— Depression mimicking hypothyroidism — must check TSH/free T4 before attributing

Step 3 management: A cancer patient on chronic opioids and pembrolizumab with new fatigue and low cortisol — distinguish opioid-induced secondary AI (slow onset, dose-related) from ICI hypophysitis (often with headache, other pituitary deficits, MRI changes); both may require glucocorticoid replacement but prognosis and ICI continuation decisions differ.

Sepsis vs. adrenal crisis in ICI patient with hypotension and fever:

Cancer progression vs. endocrinopathy for fatigue and weight loss:

Brain metastases vs. hypophysitis for headache and neurologic symptoms:

Paraneoplastic syndromes:

Other irAEs mimicking endocrine:

Drug-related causes:

Infectious causes:

Primary psychiatric:

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Hypothyroidism: levothyroxine, individualized dose; instructions for empty-stomach dosing 30–60 min before food

— Adrenal insufficiency: hydrocortisone 15–25 mg/day divided; fludrocortisone if primary; emergency injection kit (Solu-Cortef 100 mg) with patient training

— T1DM: basal-bolus insulin, glucagon emergency kit, glucometer, CGM if indicated

— Hypoparathyroidism: calcium carbonate + calcitriol

— MedicAlert bracelet/necklace for AI and diabetes — non-negotiable

— Sick day rules card (laminated, wallet-sized)

— Stress-dose steroid protocol for procedures, illness, trauma

— Self-injection training for IM hydrocortisone (patient + family member)

— Hypoglycemia symptoms and treatment for T1DM

— Annual influenza, pneumococcal (PCV20 or PCV15→PPSV23), COVID-19 boosters

— Live vaccines avoided while on high-dose steroids (>20 mg prednisone equivalent ≥2 weeks)

— Calcium 1000–1200 mg/day, vitamin D 800–1000 IU/day if on chronic glucocorticoids

— DEXA baseline if prolonged steroid use

— Statin per ASCVD risk; chronic AI increases CV mortality

— BP and lipid monitoring

— Hydration, sodium intake (especially primary AI)

— Avoid sudden discontinuation of any replacement therapy

— Endocrinology long-term follow-up

— Oncology continues ICI per response/toxicity

— PCP for general health maintenance

Board pearl: Every patient discharged with new adrenal insufficiency must leave with three items: (1) hydrocortisone tablets, (2) emergency Solu-Cortef injection kit, and (3) MedicAlert identification — failure to provide these is a board-favorite patient safety gap.

Standard discharge medications after ICI endocrinopathy:

Patient education at discharge:

Vaccinations:

Bone health:

Cardiovascular risk:

Lifestyle counseling:

Coordination of care:

Follow-Up, Monitoring Parameters, and Counseling

— Recheck TSH and free T4 6 weeks after initiating or adjusting levothyroxine

— Once stable: every 6–12 months

— Central hypothyroidism: monitor free T4, not TSH

— Clinical assessment of replacement adequacy (energy, weight, BP, electrolytes)

— Do not routinely check cortisol/ACTH to titrate glucocorticoids — clinical judgment

— Primary AI: monitor renin and electrolytes to titrate fludrocortisone (aim mid-normal renin)

— Annual reassessment for axis recovery (rare but possible)

— HbA1c every 3 months, target individualized (often <7.5%)

— Annual screening: nephropathy (urine albumin/Cr), retinopathy (dilated eye exam), foot exam, lipids

— Continuous glucose monitoring strongly recommended given brittle diabetes

— Full anterior pituitary panel at 6–12 weeks, then every 6–12 months

— Repeat MRI at 3 months if initially abnormal; no need for routine surveillance imaging if stable

— Counsel about permanence of deficits

— TSH, free T4, glucose, BMP, AM cortisol before each cycle or per institutional protocol

— Symptom screen each visit

— Permanence: most endocrine irAEs do not resolve — lifelong replacement

— Pregnancy planning for women of reproductive age

— Fertility preservation consultation if hypogonadism

— Depression/anxiety screening (PHQ-9, GAD-7)

— Sexual health discussion

— Documented MedicAlert use

— Documented sick day rules education

— Annual DEXA after 5 years of replacement

Step 3 management: At every oncology follow-up for a patient on ICI, the visit checklist must include TSH, free T4, AM cortisol (periodically), glucose, BMP, and symptom screen — anticipatory monitoring catches endocrinopathy before crisis.

Thyroid disease follow-up:

Adrenal insufficiency follow-up:

ICI-T1DM follow-up:

Hypophysitis follow-up:

Ongoing ICI cycles:

Counseling topics:

Quality measures:

Ethical, Legal, and Patient Safety Considerations

— Patients must be specifically counseled about risk of permanent endocrinopathy requiring lifelong replacement — distinct from reversible toxicities

— Combination ipi/nivo: higher irAE rate (~55% grade 3–4) — explicit discussion required

— Document discussion in chart

— Patients in adrenal crisis with altered mentation lack capacity — proceed with emergency hydrocortisone under emergency exception; obtain surrogate consent for procedures

— Goals-of-care discussion if advanced cancer: hormone replacement is always indicated (improves quality of life, prevents crisis) even in palliative settings

— Discharge from inpatient: written sick-day rules, emergency kit, direct communication to PCP and oncologist about new AI

— ED visits: any ICI patient should have AI status flagged in EHR for stress-dose protocols

— Surgical pre-op: mandatory stress-dose steroid order before anesthesia for any patient on chronic glucocorticoids

— EHR allergy/alert: "On chronic glucocorticoids — stress dose required for surgery/illness"

— Avoid abrupt steroid discontinuation — never stop physiologic replacement

— Medication reconciliation at every visit

— Serious irAEs should be reported to FDA MedWatch

— Institutional pharmacovigilance and clinical trial reporting where applicable

— Insurance coverage for emergency injection kits, CGM, and replacement hormones varies — social work involvement

— High out-of-pocket cost for compounded calcitriol — discuss alternatives

— Patients with prior endocrinopathy on ICI are often eligible for continued therapy, but enrollment in new ICI trials may exclude active irAEs

— Transparent discussion of risks/benefits

Board pearl: A pre-op patient on chronic hydrocortisone for ICI hypophysitis who does not receive stress-dose steroids and develops intraoperative refractory hypotension is a classic patient safety / system failure vignette — the answer is systems-level intervention (EHR alert, pre-op checklist), not just individual education.

Informed consent at ICI initiation:

Capacity and shared decision-making:

Transitions of care — high-risk handoffs:

Patient safety pearls:

Mandatory reporting and pharmacovigilance:

Equity and access:

Clinical trial considerations:

High-Yield Associations and Rapid-Fire Clinical Facts

— Ipilimumab (anti-CTLA-4) → hypophysitis (10–17%)

— Pembrolizumab/nivolumab (anti-PD-1) → thyroiditis (10–20%)

— Combination ipi + nivo → highest rates of all endocrinopathies, especially hypophysitis (8–13%)

— Anti-PD-1/PD-L1 → ICI-T1DM (<1% but devastating)

— Thyroiditis: 2–6 weeks

— Hypophysitis: 6–12 weeks (median ~9 weeks)

— T1DM: variable, often after 3+ cycles

— Adrenalitis (primary): anytime

— Central hypothyroidism: TSH not reliable — always check free T4 in ICI patients

— Suspect AI: draw cortisol + ACTH before steroids

— Anti-GAD positive in 40–50% of ICI-T1DM

— Low RAIU = destructive thyroiditis (not Graves)

— Endocrine irAEs rarely require ICI discontinuation

— High-dose steroids do not reverse gland destruction (except for hypophysitis mass effect)

— Replace cortisol before thyroid hormone

— Insulin is mandatory for ICI-T1DM (no role for oral agents initially)

— Development of endocrine irAE correlates with improved tumor response (melanoma, NSCLC)

— Pituitary MRI normal in 25% of hypophysitis — clinical/lab diagnosis

— HLA-DR4 associated with ICI-T1DM, similar to classic T1DM

— Growth monitoring mandatory in children with hypophysitis

— Increase levothyroxine 30% upon confirmed pregnancy

— Solu-Cortef 100 mg IM/IV is the universal first-line for crisis

Key distinction: The "suppressed TSH + low free T4" combination is central hypothyroidism, not thyroiditis — this is a hypophysitis fingerprint that mandates full pituitary axis evaluation and cortisol replacement before levothyroxine.

Drug-toxicity associations (memorize):

Timing pearls:

Lab pearls:

Management pearls:

Prognostic pearl:

Imaging pearl:

HLA association:

Pediatric pearl:

Pregnancy pearl:

Emergency pearl:

Board Question Stem Patterns

— 62yo melanoma on ipi/nivo cycle 4 with headache, fatigue, BP 88/52, Na 128, glucose 58, cortisol 1.2, ACTH low, TSH 0.3, free T4 0.5

— Answer: IV hydrocortisone 100 mg first, then levothyroxine after cortisol replaced; pituitary MRI; continue ICI when stable

— 55yo NSCLC on pembrolizumab × 4 weeks, palpitations, weight loss, TSH <0.01, free T4 3.2, low RAIU, negative TRAb

— Answer: propranolol for symptoms; no methimazole; anticipate hypothyroid phase in 4–8 weeks; continue ICI

— 48yo on nivolumab, polyuria/polydipsia, glucose 580, pH 7.18, anion gap 22, ketones positive, C-peptide undetectable

— Answer: DKA protocol (IV fluids, IV insulin, K replacement); lifelong basal-bolus insulin; check GAD/IA-2; hold ICI until stable, then resume

— Hyperpigmentation, fatigue, K 5.8, Na 130, AM cortisol 2, ACTH 450

— Answer: hydrocortisone + fludrocortisone; emergency kit + MedicAlert

— Patient on hydrocortisone 20 mg/day for prior ICI hypophysitis needs cholecystectomy

— Answer: stress-dose hydrocortisone 100 mg IV before incision, then q8h × 24h, taper to home dose

— Patient with central hypothyroidism and AI given levothyroxine alone, develops crisis

— Answer: always replace cortisol first

— Patient on chronic hydrocortisone with vomiting and fever

— Answer: double oral dose or IM Solu-Cortef 100 mg + ED if unable to tolerate PO

— Patient on ICI + opioids with fatigue and low cortisol — distinguish opioid AI from hypophysitis

— Answer: check full pituitary panel, MRI

Board pearl: When the stem mentions ICI + hyponatremia + hypotension + hypoglycemia, the answer is almost always hypophysitis with secondary adrenal insufficiency — give IV hydrocortisone 100 mg before any other intervention.

Stem 1 — Hypophysitis with crisis:

Stem 2 — Thyroiditis biphasic:

Stem 3 — ICI-T1DM with DKA:

Stem 4 — Primary AI:

Stem 5 — Pre-op patient on chronic replacement:

Stem 6 — Sequencing trap:

Stem 7 — Sick day rules:

Stem 8 — Mimics:

One-Line Recap

Immune checkpoint inhibitor endocrinopathies are common, often permanent, and managed with hormone replacement rather than immunosuppression — but require urgent recognition because untreated adrenal crisis, DKA, or myxedema can kill while ICI therapy itself can usually continue.

Drug-toxicity fingerprints: ipilimumab → hypophysitis; PD-1 inhibitors → thyroiditis; combination → both; PD-1 → ICI-T1DM (rare but DKA-prone). Baseline and pre-cycle TSH, free T4, glucose, BMP, and periodic AM cortisol are standard of care.

Sequence of replacement is life-saving: in any patient with combined central hypothyroidism and adrenal insufficiency, give hydrocortisone before levothyroxine — thyroid hormone accelerates cortisol metabolism and can precipitate adrenal crisis. Draw cortisol/ACTH before empiric steroids but never delay treatment in a crashing patient.

High-dose steroids are reserved, not routine: most endocrine irAEs require physiologic replacement only; high-dose steroids are indicated only for hypophysitis with mass effect/visual symptoms. ICI is usually continued once replacement is established — contrasting sharply with colitis or pneumonitis, where high-dose steroids and ICI discontinuation are standard.

Patient safety package at discharge: MedicAlert identification, emergency Solu-Cortef injection kit, written sick day rules, stress-dose protocols communicated to surgical/anesthesia teams via EHR alerts, and lifelong endocrinology follow-up. Anticipatory monitoring at each ICI cycle catches endocrinopathy before it becomes a crisis, and development of an endocrine irAE may actually herald improved tumor response — frame the conversation with patients accordingly.