In the setting of critical illness, the production and function of many hormones can be interrupted. As a result, new endocrine disorders may arise or preexisting endocrine disorders can become exacerbated.

The pituitary gland, or “master gland,” is a small, pea-shaped gland at the base of the brain. The anterior pituitary gland produces the majority of the hormones and is the portion of the gland that is most likely to become dysfunctional. It produces adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH).¹ The posterior gland is responsible for producing vasopressin, also called antidiuretic hormone (ADH). A lack of vasopressin can lead to diabetes insipidus, or an inability to properly concentrate urine. The posterior gland also produces oxytocin, which helps with uterine contractions.

Most cases of hypopituitarism arise from surgery or radiation, and the rest are associated with tumors of the pituitary itself or extrapituitary tumors. Important considerations of pituitary dysfunction include pituitary dysfunction after transsphenoidal hypophysectomy or craniopharyngioma, apoplexy, and Sheehan syndrome.

In 1.1% of patients with transsphenoidal hypophysectomy or craniopharyngioma resection, a triphasic response of central diabetes insipidus, syndrome of inappropriate ADH secretion (SIADH), and chronic central diabetes insipidus may occur.² Table 22-1 shows the triphasic phase after transsphenoidal hypophysectomy or craniopharyngioma resection.

Apoplexy, or pituitary hemorrhage, may present with a sudden intense headache and visual changes and/or diplopia related to optic nerve compression.^3,4 There is often loss of hormones that are secreted from the anterior pituitary gland, including ACTH, resulting in central adrenal insufficiency, with an immediate need for stress-dose steroids, in addition to neurosurgical intervention to decompress the hemorrhagic region.⁵

Sheehan syndrome is an infarction of the pituitary gland that occurs in pregnancy, typically in the setting of delivery complications (eg, excessive blood loss or severe hypotension).⁶ Sometimes it can have a subtle presentation and the diagnosis is not made until the mother fails to lactate and/or menstruate postpartum.⁷ As with pituitary apoplexy, central adrenal insufficiency is the most pressing concern, with a risk for mortality if unrecognized.

Euthyroid Sick Syndrome

Euthyroid sick syndrome refers to abnormalities of thyroid function tests secondary to critical illness and is nonindicative of an actual thyroid problem. Often, during the initial phase of illness, the TSH level becomes slightly depressed (but not undetectable), related to pituitary thyrotropin cells in the pituitary gland going into a relative state of conservation, or reduced TSH secretion.⁸ The T4 and T3 levels are also often low in the setting of critical illness, whereas the reverse T3 will be elevated.⁹ Eighty percent of T3 is produced by peripheral deiodination of T4 to T3 via 5′-monodeiodinases in muscle, the liver, and the kidneys, and this process is diminished with low calorie intake.¹⁰ T4 is low due to low levels of thyroid hormone–binding proteins or thyroxine-binding globulin (TBG) that adheres poorly to T4.¹¹ Reverse T3 is high due to inhibition of 5′-monodeiodinase acivity.¹⁰

The degree of thyroid dysfunction can often correlate with the severity of critical illness. Then, as the illness progresses and the pituitary gland recovers, the TSH may rise above the upper limit of the normal range (but typically remains below 10 mIU/L). Ultimately, the TSH will normalize within a span of several weeks. Thyroid medication is not indicated for this condition.^12,13 Table 22-2 summarizes the progressive changes seen in nonthyroidal illness.

Unless there is a strong suspicion of an actual thyroid condition, thyroid function tests should not be routinely ordered in the setting of a critical illness.

Drug-Induced Thyroiditis

Drug-induced thyroid dysfunction is secondary to interferon-α, interleukin-2 (IL-2), lithium, and amiodarone. Amiodarone, a cardiac drug used to treat arrhythmias, has been clinically associated with development of both hypothyroidism and hyperthyroidism.¹⁴ One of the reasons that amiodarone has a tendency to affect thyroid function is that it contains a large amount of iodine (roughly 35–40%),¹⁵ which is the molecule that the thyroid gland uses for its production of thyroid hormone. Given this fact, sometimes the gland uses the excess iodine to overproduce thyroid hormone, particularly if the patient has a predisposing condition, such as Graves disease. On the other hand, amiodarone has a directly destructive effect on thyroid cells. Thyroid dysfunction can occur unpredictably, even after an extended duration of amiodarone use, so routine monitoring of thyroid function tests at baseline (before starting amiodarone), as well as periodic monitoring (while on amiodarone), can be helpful.

Amiodarone-induced hypothyroidism is thought to be due to the excess iodine causing a global inhibition of all thyroid hormone production, a phenomenon known as the Wolff-Chaikoff effect. Normally, the body is able to re-equilibrate to the excess iodine load. However, in the case of amiodarone-induced hypothyroidism, the body fails to adjust or escape from the Wolff-Chaikoff effect.¹⁶ This condition is treated with levothyroxine, generally without a need to discontinue amiodarone.

Amiodarone-induced thyrotoxicosis (AIT) is typically divided into 2 subtypes (1 and 2). Type 1 is typically associated with iodine-fueled overproduction of thyroid hormone. Conversely, type 2 is typically associated with an acute destruction of thyroid tissue.¹⁷ Table 22-3 summarizes some of the diagnostic studies that are helpful in differentiating the 2 subtypes of AIT.¹⁸ Also, Figure 22-1 illustrates the radioactive iodine uptake scan features that can be seen in the 2 subtypes.

In terms of treatment, type 1 AIT is initially treated with antithyroid medications (methimazole or propylthiouracil), potentially combined with potassium perchlorate. On the other hand, type 2 AIT generally responds best to steroid treatment. In cases of unclear etiology, antithyroid medication with steroid treatment is sometimes initiated. However, in patients who remain refractory to medication, sometimes a thyroidectomy is necessary, especially in severe cases of thyrotoxicosis.¹⁹ Discontinuation of amiodarone is generally not helpful in the immediate context, as the amiodarone has a long half-life, so its effects can linger after its discontinuation.

Thyroid Storm

Severe thyrotoxicosis can have mortality rates estimated at roughly 20% to 30%.²⁰ This situation often occurs when a patient has preexisting hyperthyroidism that is exacerbated by another critical condition, such as major surgery, trauma, pregnancy, myocardial infarction, or infection. Although hyperthyroidism must be present for this diagnosis, certain clinical features also must be present to officially make this diagnosis.²¹ In addition to fever, other clinical features include (1) gastrointestinal symptoms such as nausea, vomiting, diarrhea, and jaundice; (2) neurologic symptoms such as altered mental status or coma; and (3) cardiac symptoms such as tachycardia and cardiogenic pulmonary edema. Laboratory findings include elevated T4 and/or T3 levels and suppressed TSH. There may be associated hyperglycemia, hypercalcemia, leukopenia or leukocytosis, and elevated liver function tests.

The grading system is called the Burch-Wartofsky score and ranges from a total score of 0 to 45, with a score of 25 to 44 being suggestive of a diagnosis of thyroid storm, and a score greater than 45 as highly suggestive of a diagnosis of thyroid storm.²² Details of this scoring system are listed in Table 22-4.

Treatment includes thionamides such as methimazole or propylthiouracil to block the synthesis of thyroid hormones, iodine solution started 1 to 2 hours after initiation of the antithyroid medication to block the release of the thyroid hormones and induce Wolff-Chaikoff phenomenon, beta-blockers to block adrenergic effects, corticosteroids to reduce conversion of T3 to T4 and to treat adrenal insufficiency, and aggressive intravenous fluid hydration for hemodynamic support.²³

Hashimoto Encephalopathy

Hashimoto encephalopathy (HE) is a form of relapsing encephalopathy that was first described by Sir Walter Russell Brain in 1966.²⁴ It is sometimes also referred to as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), which alludes to the presence of high titers of classic Hashimoto antibodies (thyroid peroxidase [TPO] and antithyroglobulin [TgAb]), along with the clinical utility of steroids for treatment of this condition. However, the exact pathophysiology behind this condition is still not well understood.²⁵

The typical clinical presentation of this condition occurs over a span of about 1 to 7 days, during which an individual might experience a relapsing course of encephalopathy. Some of the neurological symptoms include personality changes and/or altered mental status, mood changes, headaches, seizures, partial paralysis, tremors, ataxia, aphasia, and sleep disturbances. Although it is a very rare diagnosis, it should be considered in the differential for a patient with unexplained symptoms of encephalopathy, especially as failure to properly make this diagnosis could result in coma or death.

Myxedema Coma

Myxedema coma is a severe case of hypothyroidism that can arise in the setting of illness or another major stressor, such as trauma, myocardial infarction, pulmonary embolus, or even exposure to cold weather, particularly when an individual has preexisting untreated hypothyroidism for a prolonged interval of time.²⁶ It can have a high mortality risk of up to 40%.²⁷ It is typically characterized by a decompensated clinical state, with notable bradycardia, hypotension, hypothermia (temp < 94°F), hypoventilation, urinary retention, changes in mental status, seizures, and coma.²⁸ Electrocardiography (ECG) findings include bradycardia, low QRS voltage, T-wave inversions, QT prolongation, and first-degree atrioventricular block. Incidentally, the skin of an individual with myxedema coma may have an edematous appearance, which is due to the accumulation of intradermal proteins, rather than being true edema.²⁹ Although there is some debate over the official criteria required for a diagnosis of myxedema coma, largely due to the overall rarity of this condition, it is generally agreed that some degree of neurological impairment (ie, altered mental status) needs to be present to make this clinical diagnosis.

Patients have hyponatremia and hypoglycemia. The hyponatremia is thought to be related to decreased free water clearance from increased vasopressin excretion or decreased renal clearance. The hypoglycemia can be due to changes in metabolism from hypothyroid and/or concurrent adrenal insufficiency.

Given that it has a high mortality risk, it is imperative to initiate treatment as soon as a diagnosis is suspected, sometimes even before lab results are available. Treatment begins with empiric stress-dose steroid treatment (eg, hydrocortisone 100 mg every 8 hours), as an adrenal crisis could be precipitated if a patient has underlying adrenal insufficiency and is suddenly administered high-dose levothyroxine.^30,31 Then, a loading dose of intravenous T3 and T4 is initiated.³⁰ T4 at 200 to 400 µg intravenously (IV) is given as the initial dose, followed by 50 to 100 µg IV. T3 is given simultaneously at 5 to 20 µg, followed by 2.5 to 10 µg every 8 hours until there is clinical improvement. Serum T3 and T4 should be monitored daily. Additionally, if an individual is known to have underlying cardiovascular disease, the loading and maintenance doses of levothyroxine would be lowered.³⁰ It is also important to directly address any clinical symptoms associated with myxedema coma, such as using a warming blanket for hypothermia, administering aggressive intravenous fluids for hypotension, intubating for respiratory support, and treating any potential precipitating conditions.²⁶

Hypoglycemia is a condition in which the blood sugar drops below 55 mg/dL.³² Normally, the body has counter-regulatory mechanisms to help restore euglycemia, including reduced production of insulin, along with increased secretion of glucagon, epinephrine, growth hormone, and cortisol.³³ When there is a process that interferes with the balance of glucose and counter-regulatory hormones, then prolonged hypoglycemia may occur. Symptoms associated with hypoglycemia include autonomic symptoms such as anxiety, sweating, palpitations, tremors, and headaches, and neurologic symptoms such as fatigue, confusion, and changes in mental status including coma and seizures. Common causes are listed in Table 22-5.

The workup consists of glucose, insulin, connecting peptide (C-peptide), β-hydroxybutyrate, proinsulin, and sulfonylurea and meglitinide screen. Plasma insulin levels greater than 3 µU/mL, proinsulin levels greater than 5 pmol/L, and C-peptide levels greater than 200 pmol/L occur in insulinoma, oral hypoglycemic-induced hyperinsulinemia, insulin autoimmune hypoglycemia, and noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS). Insulinoma also has a β-hydroxybutyrate level of less than 2.7 mmol/L. Hypoglycemia from insulinoma occurs during fasting, and hypoglycemia from NIPHS occurs 2 hours after a meal. Antibodies to insulin or insulin receptors can help distinguish autoimmune hypoglycemia from insulinoma.³⁴ Hypoglycemia from insulin autoimmune hypoglycemia occurs after a meal, during fasting, or during both.³⁴ Imaging studies such as abdominal ultrasound, spiral computed tomography (CT), magnetic resonance imaging (MRI), 111In-pentetreotide imaging, and positron emission tomography (PET) are used to localize insulinoma.