| 4.1. Thyroid |
| 4.1.1. Primary hypothyroidism |
Work-up and evaluation: - TSH, with the option of also including FT4, can be checked every 4 to 6 weeks as part of routine clinical monitoring for asymptomatic patients on ICPi therapy.
- TSH and FT4 should be used for case detection in symptomatic patients.
- Low TSH with a low FT4 is consistent with central hypothyroidism. Evaluate as per hypophysitis (refer to 4.3).
- Commonly develops after thyrotoxicosis phase of thyroiditis (4.1.2).
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| Grading | Management |
| G1: TSH >4.5 and <10 milliunits/L and asymptomatic. | - Should continue ICPi with monitoring of TSH (option for FT4) every 4 to 6 weeks as part of routine care.
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| G2: Moderate symptoms, able to perform ADL. TSH persistently >10 milliunits/L. | - May continue or hold ICPi until symptoms resolve to baseline.
- Consider endocrine consultation for unusual clinical presentations, concern for central hypothyroidism, or difficulty titrating hormone therapy.
- Prescribe thyroid hormone supplementation in symptomatic patients with any degree of TSH elevation or in asymptomatic patients with TSH levels that persist over 10 milliunits/L (measured 4 weeks apart).
- Monitor TSH every 6 to 8 weeks while titrating hormone replacement to goal of TSH within the reference range.
- FT4 can be used to help interpret ongoing abnormal TSH levels on therapy, as TSH may take longer to normalize.
- Once adequately treated, repeat testing every 6 to 12 months or as indicated for a change in symptoms.
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| G3-4: Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL. | - Hold ICPi until symptoms resolve to baseline with appropriate supplementation.
- Endocrine consultation to assist with rapid hormone replacement.
- Hospital admission for developing myxedema (bradycardia, hypothermia, and altered mental status).
- Inpatient endocrinology consultation can assist with IV levothyroxine dosing, steroids, and supportive care.
- If there is uncertainty about whether primary or central hypothyroidism is present, hydrocortisone should be given before thyroid hormone is initiated.
- Myxedema coma is a life-threatening emergency requiring admission and a high level of care.
- Thyroid supplementation and reassessment as in G2.
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Additional considerations: - For patients without risk factors (ie, <70 years old, not frail, and without cardiac disease or multiple comorbidities), full replacement can be estimated using ideal body weight for a levothyroxine dose of approximately 1.6 mcg/kg/day.
- For those older than age 70 years and/or frail patients with multiple comorbidities (including cardiac disease), consider titrating up from a lower levothyroxine starting dose of 25 to 50 mcg.
- Elevated TSH can be seen in the recovery phase of thyroiditis. In asymptomatic patients with FT4 that remains in the reference range, it is an option to monitor before treating to determine whether there is recovery to normal within 3 to 4 weeks. Progression or development of symptoms should be treated as per G2.
- Development of a low TSH on therapy suggests overtreatment or recovery of thyroid function and dose should be reduced or discontinued with close follow-up.
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| 4.1.2. Thyrotoxicosis |
Work-up and evaluation: - TSH can be checked every 4 to 6 weeks as part of routine clinical monitoring for asymptomatic patients on ICPi therapy.
- TSH and FT4 should be used for case detection in symptomatic patients. T3 can be helpful in highly symptomatic patients with minimal FT4 elevations.
- Low TSH with a low FT4 is consistent with central hypothyroidism. Evaluate as per hypophysitis (refer to 4.3).
- Consider TSH receptor antibody testing if there are clinical features and suspicion of Graves' disease (eg, ophthalmopathy and T3 toxicosis).
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| Grading | Management |
| G1: Asymptomatic or mild symptoms. | - Can continue ICPi.
- Beta-blocker (eg, atenolol or propranolol) for symptomatic relief.
- Close monitoring of thyroid function every 2 to 3 weeks after diagnosis to catch the transition to hypothyroidism, the most common outcome for transient subacute thyroiditis.
- Treat transition to elevated TSH and low FT4 as for primary hypothyroidism (refer to 4.1.1).
- For persistent thyrotoxicosis (>6 weeks) consider endocrine consultation for additional work-up.
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| G2: Moderate symptoms, able to perform ADL. | - Consider holding ICPi until symptoms return to baseline.
- Consider endocrine consultation.
- Beta-blocker (eg, atenolol or propranolol) for symptomatic relief.
- Hydration and supportive care.
- For persistent thyrotoxicosis (>6 weeks) refer to endocrinology for additional work-up and possible medical thyroid suppression.
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| G3-4: Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL. | - Hold ICPi until symptoms resolve to baseline with appropriate therapy.
- Endocrine consultation for all patients.
- Beta-blocker (eg, atenolol or propranolol).
- Hydration and supportive care.
- Consider hospitalizing patients in severe cases as inpatient endocrine consultation can guide the use of additional medical therapies including steroids, SSKI, or thionamide (methimazole or propylthiouracil) and possible surgery.
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Additional considerations: - Thyroiditis is self-limited and the initial hyperthyroidism generally resolves in weeks with supportive care, most often to primary hypothyroidism or occasionally to normal. Persistent or symptomatic hypothyroidism developing after hyperthyroidism should be treated as above (4.1).
- GD has not been reported with ICPi specifically, but sporadic cases could occur. GD is generally persistent and is treated with antithyroid medical therapy, radioactive iodine, or surgery. Endocrine consultation is recommended if suspected.
- Physical examination findings of ophthalmopathy or thyroid bruit are diagnostic of Graves' disease and should prompt early endocrine referral.
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| 4.2. Adrenal – primary AI |
Work-up and evaluation: - Evaluate AM levels of ACTH (if >2 times ULN) and cortisol level (if >3 mcg/dL).
- Basic metabolic panel (Na, K, CO2, and glucose).
- Renin and aldosterone.
- Consider standard dose ACTH stimulation test for indeterminate results (AM cortisol >3 mcg/dL and >15 mcg/dL).
- Evaluate for precipitating cause of crisis such as infection.
- Adrenal CT for metastasis or hemorrhage (most common causes of primary AI).
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| Grading | Management |
| All grades. | - Referral to endocrinology.
- Education on steroid stress dosing, emergency injections, and a medical alert bracelet or necklace, accessory, or system.
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| G1: Asymptomatic or mild symptoms. | - Consider holding ICPi until patient is stabilized on replacement hormone.
- Endocrine consultation.
- Initiate replacement therapy with hydrocortisone (15 to 20 mg/day in divided doses – refer to additional considerations).
- Titrate hydrocortisone to maximum of 30 mg/day for residual symptoms of AI.
- Reduce maintenance dosing for symptoms of iatrogenic Cushing's syndrome (eg, bruising, thin skin, edema, weight gain, hypertension, and hyperglycemia).
- Most primary AI will also require fludrocortisone (starting dose 0.05 to 0.1 mg/day). Adjust based on volume status, sodium level, and renin response (target upper half of the reference range).
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| G2: Moderate symptoms, able to perform ADL. | - Consider holding ICPi until patient is stabilized on replacement hormone.
- Endocrine consultation.
- See in clinic to assess need for hydration, supportive care, and hospitalization.
- Initiate outpatient corticosteroid treatment at 2 to 3 times maintenance (eg, hydrocortisone 30 to 50 mg/day in divided doses or prednisone 20 mg daily) to manage acute symptoms.
- Initiate fludrocortisone (0.05 to 0.1 mg/day).
- Decrease stress dose corticosteroids down to maintenance doses after 2 days.
- Maintenance therapy as in G1.
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| G3-4: Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL. | - Hold ICPi until patient is stabilized on replacement hormone.
- Endocrine consultation.
- Inpatient management may be needed to provide:
- Normal saline (at least 2 L).
- IV Stress dose steroids: hydrocortisone 50 to 100 mg every 6 to 8 hours initial dosing.
- Taper stress dose corticosteroids down to oral maintenance doses over 5 to 7 days.
- Maintenance therapy as in G1.
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Additional considerations: - Primary and secondary adrenal insufficiency can be distinguished by the relationship between ACTH and cortisol. If the ACTH is low with low cortisol, then management is as per hypophysitis in section 4.3 for secondary (central) adrenal insufficiency.
- Using hydrocortisone allows for recreation of the diurnal rhythm of cortisol. Typically, two-thirds of the dose is given in the morning and one-third of the dose in the early afternoon. Long-acting steroids such as prednisone, rather than short-acting hydrocortisone, carry risk of over replacement but can be used in special circumstances, for example, if a patient is not able to adhere to a short-acting steroid regimen. Hydrocortisone 20 mg is equivalent to prednisone 5 mg.
- DHEA replacement is controversial but deficiency can be tested and replacement considered in women with low libido and/or energy who are judged to be otherwise well replaced.
- All patients need education on stress dosing for sick days, use of emergency injectables, when to seek medical attention for impending adrenal crisis, and a medical alert bracelet or necklace for adrenal insufficiency to trigger stress dose corticosteroids by emergency medical personnel. Therefore, early endocrinology consultation is appropriate.
- Endocrine consultation should be part of planning before surgery or high-stress treatments such as cytotoxic CTX at any time during a patient's care.
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| 4.3. Pituitary – hypophysitis |
Work-up and evaluation: - Evaluate ACTH (AM), cortisol (AM), TSH, free T4, and electrolytes.
- Consider standard-dose ACTH stimulation testing for indeterminate results (AM cortisol >3 mcg/dL and <15 mcg/dL).
- Consider evaluating LH and testosterone in males, FSH, and estrogen in premenopausal females with fatigue, loss of libido and mood changes, or oligomenorrhea.
- Consider MRI brain with or without contrast with pituitary or sellar cuts in all patients with new hormonal deficiencies and particularly those with multiple endocrine abnormalities ± new severe headaches or complaints of vision changes.
- Perform MRI brain with or without contrast with pituitary or sellar cuts for all patients presenting with diabetes insipidus (DI is most commonly from metastatic disease).
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| Grading | Management |
| All grades. | - Referral to endocrinology.
- Education on steroid stress dosing, emergency injections, and a medical alert bracelet or necklace, accessory, or system.
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| G1: Asymptomatic or mild symptoms. | - Consider holding ICPi until patient is stabilized on replacement hormones.
- Endocrine consultation.
- Corticosteroid replacement for adrenal insufficiency with preference for hydrocortisone (15 to 20 mg/day in divided doses – refer to additional considerations section 4.2).
- Initiate other hormone replacement only after any needed adrenal replacement to avoid precipitating adrenal crisis:
- Thyroid hormone replacement if needed using dosing as above for primary hypothyroidism, with a goal FT4 in the upper half of the reference range (TSH is not accurate in central hypothyroidism).
- Testosterone or estrogen therapy if needed in those without contraindications (eg, prostate cancer, breast cancer, or history of DVT).
- Recommend education on stress dosing, emergency injectable, and a medical alert or necklace accessory or system.
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| G2: Moderate symptoms, able to perform ADL. | - Consider holding ICPi until patient is stabilized on replacement hormones.
- Endocrine consultation.
- Clinic evaluation to assess need for steroids and volume repletion.
- Consider oral pulse dose therapy in patients with MRI findings of swelling or threatened optic chiasm compression (prednisone 1 mg/kg/day [or equivalent]). Taper over 1 to 2 weeks and transition to physiologic maintenance therapy once down to 5 mg prednisone equivalent.
- Hormonal supplementation as in G1.
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| G3-4: Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL. | - Hold ICPi until patient is stabilized on replacement hormones.
- Endocrine consultation.
- Hospitalize or make an ED referral for:
- Normal saline (at least 2 L) or monitored free water replacement if DI.
- IV Stress dose steroids: hydrocortisone 50 to 100 mg every 6 to 8 hours initial dosing.
- Oral pulse dose therapy with Prednisone 1 to 2 mg/kg daily (or equivalent) tapered over at least 1 to 2 weeks to physiologic maintenance in patients with significant swelling on MRI, optic chiasm compression, severe headache, or visual changes.
- Taper stress dose corticosteroids down to oral maintenance doses over 5 to 7 days.
- Maintenance therapy as in G1.
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Additional considerations: - Please be aware of the need to start corticosteroids first when planning hormone replacement therapy for multiple deficiencies as other hormones accelerate the clearance of cortisol and can precipitate adrenal crisis.
- ACTH stimulation can give a false-negative result early in hypophysitis as adrenal reserve declines slowly after pituitary stimulation is lost. In the presence of clinical uncertainty, opt for replacement and test for ongoing need at 3 months.
- If prednisone or equivalent is started for mild or moderate symptoms, consider lower doses (average daily dose over two months of <7.5 mg) because of report of reduced survival on higher doses.
- All patients need education on stress dosing for sick days, use of emergency steroid injectables, when to seek medical attention for impending adrenal crisis, and a medical alert bracelet for adrenal insufficiency to trigger stress dose corticosteroids by EMS.
- Steroid use for other irAEs can cause isolated central adrenal insufficiency with a low ACTH. In a patient with adrenal insufficiency, a recent history of treatment with corticosteroids, and no other central hormone deficiencies, the HPA axis should be tested for recovery after 3 months of maintenance therapy with hydrocortisone.
- Laboratory confirmation of AI should not be attempted in patients given high-dose corticosteroids for other irAEs until treatment is ready to be discontinued.
- AM cortisol in a patient on corticosteroids is not diagnostic as the measurement of therapeutic steroids in the assay for cortisol varies. Hydrocortisone needs to be held for 24 hours and other steroids for longer before endogenous function is assessed. Consider consulting endocrinology for recovery and weaning protocols using hydrocortisone in patients with symptoms of AI after weaning off corticosteroids.
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| 4.4. Diabetes |
Work-up and evaluation: - Monitor patients for symptoms of new or worsening DM (polyuria, polydipsia, and fatigue).
- Monitor glucose at baseline and with each treatment cycle while on therapy and at follow-up visits for at least 6 months.
- Laboratory evaluation in suspected CIADM should include:
- Urine and/or serum ketones.
- Anion gap on a metabolic panel.
- Anti-GAD or anti-islet cell antibodies.
- C-peptide levels.
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| Grading | Management |
| G1: Asymptomatic or mild symptoms; T2DM with fasting glucose value >ULN to 160 mg/dL (>ULN to 8.9 mmol/L). No evidence of CIADM such as ketoacidosis or laboratory evidence of pancreatic autoimmunity. | - Can continue ICPi with close clinical follow-up and laboratory evaluation.
- Refer to PCP for additional management or:
- May initiate oral therapy for those with new-onset T2DM.
- Intensify medical therapy for those with worsening T2DM.
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| G2: Moderate symptoms, able to perform ADL; T2DM with fasting glucose value >160 to 250 mg/dL (>8.9 to 13.9 mmol/L). No ketoacidosis or metabolic derangements but other evidence of CIADM at any glucose level. | - May hold ICPi until glucose control is obtained.
- Urgent endocrine consultation for any patient with new-onset CIADM.
- Initiate insulin for CIADM (or as default therapy if there is any question about the diagnosis).
- Referral to ED or hospital admission if unable to initiate therapy, urgent outpatient specialist evaluation is not available, developing ketoacidosis, or other concern for CIADM.
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| G3-4: Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL; G3: >250 to 500 mg/dL (>13.9 to 27.8 mmol/L); G4: >500 mg/dL (>27.8 mmol/L). Ketoacidosis or other metabolic abnormality. | - Hold ICPi until glucose control is obtained with reduction of toxicity to ≤G1.
- Admit for inpatient management of DKA, volume and electrolyte resuscitation, and insulin initiation.
- Endocrine consultation for all patients.
- Insulin therapy appropriate for all patients.
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Additional considerations: - Insulin therapy should be used in any case with significant hyperglycemia pending additional diagnostic work-up if mechanism of DM is not known.
- Long-acting insulin therapy alone is not sufficient for CIADM because of the absence of pancreatic function after beta-cell destruction:
- Starting total daily requirement can be estimated at 0.3 to 0.4 units/kg/day.
- Half of daily requirements are typically given in divided doses as prandial coverage, while half should be administered as a once-daily long-acting analog. This requires self-monitoring 4 or more times daily or the use of a continuous glucose monitor.
- Sliding scale insulin can be used in conjunction with multiple daily injection regimens to accommodate the variability in glucose levels.
- Decreased requirements after the initial acute admission for DKA are commonly seen in the so-called honeymoon period.
- Education is critical to learn skills like responding to hypoglycemia, anticipating exercise, monitoring for DKA, or carbohydrate counting, and to transition to technologies such as insulin pumps. Early endocrinology consultation is a high priority for all patients.
- T2DM patients will need to increase the frequency of self-monitoring as therapy intensifies and agents that can cause hypoglycemia are added to their regimen.
- Steroids can exacerbate postprandial hyperglycemia, and endocrinology consult should be considered for initiating or managing insulin in patients with T2DM being started on high-dose steroids. If insulin is used, the doses generally needs to be adjusted again as steroids are tapered down.
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