**4. Thyroid dysfunction**

Immunotherapy related thyroid dysfunction can range from painless thyroiditis with transient thyrotoxicosis, transient or long-standing hypothyroidism, thyroid associated orbitopathy, and occasionally thyroid storm [27–29].

#### **4.1 Incidence**

Thyroid disorder can present with nonspecific symptoms such as fatigue and weakness. It is important to distinguish between primary versus secondary hypothyroidism, as former is more likely with anti-PD-1 and anti-PD-L1 mAbs with incidence ranging from 4–19.5%; and later is more suggestive from hypophysitis induced by anti-CTLA-4 mAbs [30].

For patients treated with nivolumab and pembrolizumab, the incidence rates of hypothyroidism were similar at 6.5% and 7.9% respectively. Incidence rate for hypothyroidism with ipilimumab, nivolumab or pembrolizumab, atezolizumab, and the combination of ipilimumab plus nivolumab were 3.8, 7.0, 3.9, and 13.2 percent, respectively [31].

Primary hyperthyroidism is seen less frequently with immunotherapy with incidence rates for hyperthyroidism with ipilimumab, nivolumab or pembrolizumab, atezolizumab, and the combination of ipilimumab plus nivolumab were 1.7, 3.2, 0.6, and 8 percent, respectively [31].

#### **4.2 Monitoring**

Baseline thyroid function test should be obtained before initiation of immunotherapy and after that regular monitoring of thyroid hormone levels including TSH and free T4 is recommended before each treatment and also when symptoms arise.

#### **4.3 Diagnosis**

High TSH with low free T4 indicates primary hypothyroidism and a low TSH and low free T4 indicates hypophysitis. In thyroiditis with transient thyrotoxicosis low TSH and high free T4 may be followed by more long-standing hypothyroidism high TSH and low free T4.

#### **4.4 Treatment**

While asymptomatic patients with mildly elevated TSH level < 10 can be observed, thyroid hormone replacement remains the mainstay of treatment in hypothyroidism. Dosage adjustment should be done every 4–6 weeks based on TSH level. Patients with thyroiditis and transient thyrotoxicosis can be managed symptomatically with beta blockers. Immunotherapy can be continued except and case of severe thyrotoxicosis when drug might need to be paused until symptoms resolve. Many patients may have subclinical hypothyroidism (TSH >20 mIU/L and normal T4) with symptoms, and in our experience, this should be treated with close monitoring for clinical improvement.

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*The Endocrinological Side Effects of Immunotherapies DOI: http://dx.doi.org/10.5772/intechopen.96491*

The adrenal insufficiency with immunotherapy is rare [32], there have been case reports which showed the association of immunotherapies and adrenal insufficiency. Data shows that there is a risk of 0.8–1.6% of adrenal insufficiency with ipilimumab either as a monotherapy or combination with anti-PDL 1 therapy. There is a 1% risk of primary adrenal insufficiency with nivolumab and median time of onset is around 4.5 months. Data suggests that there is 0.5% risk of primary adrenal insufficiency with avelumab and 0.4% risk of adrenal insufficiency in patients with atezolizumab. There have been reports of subclinical form of adrenalitis with immune check point inhibitors, with normal endocrine function but radiographic evidence of inflammation of adrenal glands known as adrenalitis-symmetrically enlarged and

It is very rare to have primary adrenal insufficiency associated with adrenal crisis. Characteristic findings may include weight loss, fatigue, anorexia, nausea, vomiting, abdominal pain, orthostatic hypotension, hypoglycemia, eosinophilia,

Low or suppressed morning serum cortisol with high ACTH levels will be seen

Adrenal crisis is one of the most serious and life-threatening endocrinological side effect of immunotherapy, which requires prompt diagnosis and treatment. If there is high clinical suspicion of adrenal crisis, after obtaining serum cortisol and ACTH levels, treatment should be started without waiting for the results to come back. Patients should be given stress doses of steroids, IV hydrocortisone 100 mg every six to eight hours and aggressive fluid resuscitation should be made as there is high risk of hypovolemic shock. Endocrinologist consult is highly recommended

Type 1 diabetes mellitus is also a rare a side effect in patients treated with immunotherapy. Type 1 DM has been observed in around 1% of patients treated with nivolumab and in 0.2% of patients treated with pembrolizumab. The median

Type 1 DM is rare but when present, ketoacidosis must be investigated and

time of onset from starting immunotherapy is around 4.5 months.

treated [34]. Anti-GAD65 can be performed to look for autoimmunity.

hyperpigmentation, hyponatremia, hyperkalemia or hypercalcemia.

**5. Primary adrenal insufficiency**

smooth adrenal glands [33].

**5.2 Characteristic findings**

in patients with adrenal insufficiency.

**6. Type 1 diabetes mellitus**

**5.3 Diagnosis**

**5.4 Treatment**

as well.

**6.1 Incidence**

**6.2 Diagnosis**

**5.1 Incidence**
