Summary of the adverse endocrine effects of immune checkpoint inhibitors
| Gland | Incidence15,16 | Most commonly associated checkpoint inhibitors 3,16 | Typical time from treatment onset16 | Symptoms16,45 | Screening advised? | Suggested Investigations3,17 | Treatment3,17 | Prognosis16 |
|---|---|---|---|---|---|---|---|---|
| Thyroid | Hypothyroid: overall 8%, combination up to 13% Hyperthyroid: overall 2.9%, combination 8% | Anti PD-1 mAb or combination | 6 weeks (range 4–10 weeks) | Hypothyroid: fatigue, dry skin, constipation, depression, cold sensitivity, weight gain Hyperthyroid: fatigue, palpitations, diarrhoea, anxiety, insomnia, weight loss | TSH with every cycle or monthly, and 4–6 weeks after final cycle | TSH, T4, T3 Consider pituitary screen if abnormal If thyrotoxicosis: anti-TPO Ab, anti-TSHR Ab, cortisol, glucose If clinical uncertainty: thyroid uptake scan | Hypothyroid: Continue immunotherapy Hyperthyroid: continue immunotherapy if asymptomatic, hold if symptomatic and restart when symptoms resolve See Fig 2 | Typical disease course 3–6 weeks hyperthyroid, then prolonged hypothyroid Two-thirds required long-term thyroid replacement Hyperthyroidism rarely persists |
| Pituitary | Overall 1.3%, combination 6.4% | Anti-CTLA-4 mAb or combination | 12 weeks (range 3–72 weeks) | General: fatigue, nausea Hormone deficiency: hypothyroid (see thyroid), low cortisol (see adrenal) and sex hormone deficiency (erectile dysfunction, menstrual disturbance, loss of libido) Mass effect: headache, visual loss | Nil Low threshold for screening | Cortisol (ideally 9am, random if unwell), ACTH, TSH, T4, LH/FSH, oestradiol (if premenopausal), testosterone (men), IGF-1, prolactin MRI pituitary | Hold immunotherapy until symptoms controlled, then most can restart Continue if asymptomatic See Fig 3 | Secondary adrenal insufficiency (ACTH deficiency) mainly irreversible Thyroid and sex hormones tend to recover within 3 months |
| Pancreas | Overall 0.5%, 1% with anti-PD-1/anti-PD-L-1 | Anti-PD-1 or Anti-PD-L-1 mAb | 7 weeks (range 1–52 weeks) | Thirst, polyuria, fatigue, weight loss Two-thirds present with DKA | Regular blood glucose monitoring | Glucose, ketones, Hba
1c, C-peptide, anti-GAD Ab, ICA Ab No imaging advised | Hold while blood glucose uncontrolled, restart once insulin initiated or stable Most need insulin therapy. If mild, trial oral antihyperglycaemic agents | Irreversible |
| Adrenal | Monotherapy 1% Combination 5–7% | Anti-PD-1 or Anti-CTLA-4 mAb or combination | 10 weeks (range 1–36 weeks) | Fatigue, dizziness, weakness, nausea, abdominal pain | Nil Low threshold for 9am cortisol | Cortisol, ACTH, TFT CT adrenals | High-dose steroids initially, wean to hydrocortisone 20–30 mg/day Fludrocortisone if postural hypotension persists | Irreversible |
ACTH = adrenocorticotrophic hormone; CTLA-4 = cytotoxic T-lymphocyte antigen 4; FSH = follicular stimulating hormone; GAD = glutamic acid decarboxylase; ICA = islet cell antigen; IGF-1 = insulin-like growth factor 1; LH = luteinising hormone; mAb = monoclonal antibody; PD-1 = programmed cell death protein 1; PD-L-1 = programmed cell death protein ligand 1; T4 = thyroxine; T3 = triiodothyronine; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone; TSHR = thyroid-stimulating hormone receptor.