Chapter 14. Endocrinology

Diabetic ketoacidosis/ketoacidemia (DKA) is an absolute or relative insulin deficiency resulting in ketone body production and decreased serum total CO2 concentration. This potentially life-threatening metabolic disturbance occurs most commonly in type 1 diabetics, but may also occur in type 2 diabetics.

Absolute or relative insulin deficiency results in hyperglycemia, glycosuria, and intracellular starvation, leading to release of counterregulatory hormones (glucagon, epinephrine, cortisol, and growth hormone). This results in lipolysis, proteolysis, glycogenolysis, gluconeogenesis, and insulin resistance. Glycogenolysis and gluconeogenesis exacerbate the already-present hyperglycemia. A negative cycle of progressive ketoacidemia and insulin resistance, associated with a surge of counterregulatory hormones, leads to increasing insulin resistance, hyperglycemia, dehydration, electrolyte losses, potential brain swelling, and may result in metabolic death.

Clinical Features

Key findings include polyuria, nocturia, polydipsia, no change in appetite, polyphagia or decreased appetite, varying degrees of dehydration, weight loss, abdominal pain, vomiting, hyperventilation, Kussmaul breathing (which is clinically visible and may be confused with respiratory distress from primary respiratory diseases such as pneumonia), subnormal body temperature (in severe DKA; may also occur in sepsis), altered mental status (which may be caused by shock, profound ketoacidemia or raised intracranial pressure [ICP]), the fruity odor of ketones on the breath, and Candida infections (eg, vaginitis or perineal yeast). Typical laboratory findings include hyperglycemia (may only be modest with serum glucose <300 mg/dL), glycosuria, ketonemia, ketonuria, metabolic acidosis/acidemia, and compensatory hypocarbia. Enuresis, urinary incontinence, apparent or actual hyponatremia, hypernatremia, hypokalemia, hypophosphatemia, hypomagnesemia, increased serum urea nitrogen, increased serum creatinine, hypertriglyceridemia, and increased serum amylase may also be present. Increased lipase in the absence of pancreatitis may occur. Initially, potassium, magnesium, and phosphorus may be increased or normal; however, close monitoring is required because serum concentrations of these ions may decrease significantly with treatment as they move intracellularly, and total body depletion of one or more of these ions becomes manifest.

The degree of dehydration varies in DKA. Severe DKA (ie, severe ketoacidemia) does not necessarily mean that severe dehydration is present; the degree of ketonemia and the degree of dehydration should be individually assessed. Raised ICP is the most common cause of morbidity and mortality; thus, monitoring for neurologic symptoms is essential. Avoid excessive volume administration, which can exacerbate brain swelling. Efforts to assign a volume of deficit should be made (Table 14.1).

Emergency Department Treatment and Disposition

Airway, breathing, and circulation must be addressed and insulin therapy begun. In rare cases where tracheal intubation is indicated, it should be accomplished using techniques that are protective for patients at risk for raised ICP. In addition, such patients are often profoundly hypocarbic (some patients have Paco2 values in the single digits). Their degree of compensatory hyperventilation should be maintained once the patient is intubated to avoid further decreases in blood and possibly cerebrospinal fluid (CSF) pH, which itself may contribute to brain swelling.

If shock is present, emergency volume resuscitation is required (Figure 14.1 and Table 14.1). A requirement for more than 30 mL/kg of isotonic saline resuscitation fluid is uncommon and the need for emergency volumes in excess of 20 to 30 mL/kg of ideal body weight should raise suspicion of significant complicating illnesses such as septic shock, pancreatitis, or severe enteritis. Severe ketonemia causes vasoconstriction. Cool, sometimes mottled, skin may be attributable to a very low blood pH rather than hypovolemia. For this reason, if foot pulses are strong and blood pressure is appropriate but skin remains cool and/or mottled despite 10 to 20 mL/kg of resuscitation fluid in the presence of severe acidemia, further bolus volume resuscitation may not be warranted. In these cases, insulin and rehydration therapy is recommended with serial reassessments; impaired perfusion should resolve as ketonemia is corrected with insulin and gradual rehydration. For the remainder of hydration, use solutions as described in Figure 14.6.

Monitor closely for signs of raised ICP, including lethargy, altered mental status, decreased arousability, age-inappropriate bed-wetting associated with lack of awareness, headache, hypertension, bradycardia or relative bradycardia for the clinical situation, pupillary sluggishness or unresponsiveness, anisocoria, new focal neurologic signs, and/or seizures. If raised ICP is suspected, treat with hypertonic (20% or 25%) mannitol 0.25 to 1 g/kg over 20 minutes and evaluate the patient for a decrease in volume delivery (ie, consider a decrease in the rate of intravenous [IV] fluid infusion). If hemodynamic instability is present, infusion of 3% NaCl (3-10 mL/kg) may be an alternative to use of an osmotic diuretic. Tracheal intubation with an appropriate degree of hyperventilation may also be required.

Initiate treatment with insulin as soon as possible (by the end of the first treatment hour) by continuous intravenous infusion of regular human insulin 0.1 unit/kg actual (not ideal) body weight per hour. An improvement in the base deficit by 1 mEq/L/hour indicates adequate insulin dosing and delivery. Failure to achieve this goal suggests an inadequate insulin dose or a problem with insulin delivery (eg, adsorption of insulin to IV tubing, infiltrated IV site, malfunction of the IV pump). The insulin dose should be increased by increments of 100% if ketoacidosis is not improving. If the patient is using an insulin pump and presents with DKA, treat with continuous IV insulin even if the pump appears to be functioning.

While DKA is most commonly triggered by treatment noncompliance, it is also important to rule out other triggers including infections, acute abdominal processes, depression, behavioral disorders, illicit drug use, pregnancy, psychosocial problems, and physical and sexual abuse.

Patients should be admitted to the ICU and after stabilization, a diabetes nurse educator and nutritionist should be involved in team care.

Pearls

1. Watch closely for altered mental status and signs of cerebral edema or increased ICP; treat suspected increased ICP with mannitol and then obtain head CT.

2. Do not assume that severe acidemia is necessarily associated with severe dehydration or that the parched oral mucosa commonly seen with Kussmaul breathing and severe acidemia is indicative of severe dehydration.

3. Give emergency volume resuscitation only in the presence of shock.

4. Failing to recognize that concomitant illness such as pancreatitis, sepsis, acute abdomen, etc may be present and masked.

5. A continuous infusion of insulin at effective doses must be given by the end of the first treatment hour. Deep intramuscular (IM) administration of regular insulin 0.1 units/kg given hourly may be used as a bridge to continuous IV infusion in situations where IV access or appropriate monitoring cannot be optimally achieved (eg, certain transport situations).

6. Do not give antiemetics as these can mask the neurologic status; vomiting and abdominal pain caused by DKA are treated by insulin and fluid administration; if vomiting and abdominal pain continue, consider confounding illness.

7. If serum glucose is <250 mg/dL in the presence of ketoacidosis, increase glucose delivery so that insulin can be continued to correct ketoacidosis.

8. Hyperosmolar hyperglycemic syndrome presents with marked hyperglycemia (usually >800 mg/dL), minimal or mild ketosis(less severe than DKA), and dehydration (typically more severe than DKA). The principles of management are similar as for DKA. Some patients have underlying diabetes (often type 2), but not all patients are diabetic. However, most patients will require insulin therapy during the acute illness.

The authors acknowledge the special contributions of Binita R. Shah, MD, to prior edition.

Clinical Summary

Addison disease is an adrenocortical insufficiency due to destruction of the adrenal cortex, most commonly caused by autoimmunity followed by tuberculosis. Acute Addisonian crisis is a medical emergency that presents with nausea, vomiting, and shock. Patients may also present with hyperpyrexia, confusion, or even coma. Physical examination may reveal hyperpigmentation of the skin and mucous membranes. Addisonian crisis may be precipitated by stressors such as infection, surgery, trauma, or emotional stress. Iatrogenic causes include failure to increase steroid dose and bilateral removal of the adrenals. Other causes include adrenal hemorrhage secondary to severe bacterial infection, bilateral artery emboli, or bilateral vein thrombosis secondary to hypercoagulable state. The differential diagnosis includes adrenal hemorrhage, histoplasmosis, sarcoidosis, tuberculosis, congenital adrenal hyperplasia, bacterial or fungal sepsis, secondary adrenocortical insufficiency, and other shock states (eg, trauma, hemorrhage).

A random cortisol level should be drawn before the treatment with steroids is initiated in patients with suspected adrenal crisis. Other laboratory tests should include comprehensive metabolic panel, CBC, thyroid function. Obtain chest radiograph to exclude tuberculosis (TB) or fungal infections as well as to assess the heart size. Consider abdominal CT scan to assess adrenal size and to exclude adrenal hemorrhage. Adrenal glands are enlarged with adrenal hemorrhage or infiltrative disease and small and atrophic with autoimmune Addison disease. Calcification of adrenal glands may be present in patients with TB.

Emergency Department Treatment and Disposition

Resuscitate patients with Addisonian crisis giving fluid boluses with crystalloids for the treatment of hypotension and shock, as clinically indicated, until stabilization of vital signs. Begin stress doses of IV glucocorticoids in the ED (dose: 2 mg/kg or rough estimate as follows: 25 mg for infants, 50 mg for small children, and 100 mg for adolescents). It is always better to overestimate the dose rather than underestimate it. Hospitalize patient to ICU for continuous cardiovascular monitoring and further management and consult endocrinology.

Pearls

1. Consider adrenal insufficiency in a patient with increased pigmentation of the skin.

2. Hyperpigmentation may be equally intense over entire body or accentuated in sun-exposed areas. Failure of a suntan to disappear may be an important clue.

3. The most common cause of Addison disease is autoimmunity. TB should be suspected in high-risk patient population.

4. IV fluid resuscitation is still the first line of treatment of Addisonian crisis.

5. Cortisol levels should be obtained before treatment with steroids is initiated.

Clinical Summary

Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders that affects enzymes of adrenal steroidogenesis. Clinical manifestation varies depending on the degree of cortisol and/or aldosterone deficiency and enzyme involvement. The most common form of CAH is 21-hydroxylase deficiency that can present as classical (presenting with salt wasting in boys and girls and ambiguous genitalia in girls), simple virilizing, and nonclassical CAH (late onset, presenting with hirsutism in girls and precocious puberty in boys). The second most common form of CAH is due to 11-β-hydroxylase deficiency. The other less common forms of CAH include 17-α-hydroxylase, 20,22-desmolase, and 3-β-hydroxysteroid dehydrogenase deficiency.

Adrenal or salt wasting crisis is a medical emergency presenting with hyponatremia, hyperkalemia, dehydration, and hypotension, with or without hypoglycemia. Girls with classical CAH are diagnosed in the nursery because of ambiguous genitalia; boys might be easily missed in places where antenatal screening is not implemented. However, mild forms of classical CAH may become apparent later in childhood during the stress related to illness, surgery, or trauma.

The differential diagnosis include but are not limited to adrenal hypoplasia, adrenal insufficiency, pyloric stenosis, sepsis, failure to thrive, cystic fibrosis, adrenal hemorrhage, renal salt wasting, small bowel obstruction, and other shock states.

Laboratory analysis should include comprehensive metabolic panel, CBC, as well as cortisol, 17-hydrohyprogesterone (17OHP), and aldosterone levels. No specific imaging studies are necessary for diagnosis of CAH.

Emergency Department Treatment and Disposition

Patients with salt wasting crisis due to CAH should be volume resuscitated with isotonic fluids as clinically indicated. Consider dextrose in case of hypoglycemia. Glucocorticoid treatment should be initiated immediately. Delaying treatment can be life-threatening. Stress doses of injectable glucocorticoids should be given IV in the ED. (Dose: 2 mg/kg or a rough estimate as follows: 25 mg for infants, 50 mg for small children, and 100 mg for adolescents.) Hospitalize patient to ICU and consult endocrinology for further evaluation and management.

Pearls

1. Consider CAH in case of hypotension and shock after seemingly minor stress.

2. Consider obtaining cortisol levels before treatment when steroids are initiated.

3. Treat with IV fluid bolus and injectable glucocorticoids without waiting for the blood results.

4. It is always better to overestimate the dose of steroids rather than underestimate it.

Clinical Summary

Acquired hypothyroidism is a common disorder seen in adolescents. Hypothyroidism in children usually presents with nonspecific symptoms such as fatigue, sluggishness, and decreased school performance. Other complaints are constipation, hair loss, muscle weakness, menstrual irregularities, joint pain or stiffness, and depressed mood. There may also be a decrease in growth velocity with appropriate or accelerated weight gain or delayed pubertal development. Coarse facial features, goiter, dry skin, and nonpitting edema are other findings. If hypothyroidism is not treated, the signs and symptoms become more severe with the development of advanced hypothyroidism, that is, myxedema that manifests as nonpitting edema, hyporeflexia, pericardial effusion associated with hypotension, bradycardia, hypothermia, decreased work of breathing, and even coma.

In developing areas of the world, iodine deficiency remains the primary cause of hypothyroidism; in developed countries, autoimmune disease is much more prevalent. Congenital hypothyroidism is detected by the universal newborn screen in most cases in developed countries; when not detected by newborn screen, it may become apparent at 2 to 3 years of age. After the age of 3 years, autoimmune thyroiditis remains the most common cause of hypothyroidism.

Hypothyroidism may be primary (high TSH levels with a low or normal free T4 levels) and secondary or central (normal or low TSH levels with a low free T4 levels). Primary hypothyroidism can be autoimmune, postpartum, subacute or inflammatory thyroiditis, iatrogenic, or drug mediated and secondary to iodine deficiency or excess and rarely, due to inborn errors of thyroid hormone synthesis. Secondary or central hypothyroidism is rare and should be considered with history of head trauma or cranial radiation, pituitary adenoma, or with other pituitary hormone deficiencies.

Laboratory evaluation should consist of TSH and free T4 levels. Imaging studies (ultrasound and or nuclear scan) may be helpful in congenital hypothyroidism.

Emergency Department Treatment and Disposition

Myxedema is a life-threatening condition, and admission to an intensive care unit is warranted. Workup should include CBC, blood cultures, serum electrolytes, and cortisol levels. Intravenous thyroid hormone replacement can be started while waiting for confirmatory results. In case of multiple pituitary hormone deficiencies, steroids should be administered prior to thyroid hormone replacement to prevent adrenal crises.

Patients with acquired hypothyroidism without myxedema should be referred to the endocrinologist for prompt treatment. When levels of TSH and free T4 are readily available in the emergency department (ED), maintenance therapy with levothyroxine should be started.

Pearls

1. High index of suspicion is required for diagnosis of hypothyroidism because of nonspecific signs and symptoms.

2. The most common cause of hypothyroidism in children and adolescents is Hashimoto thyroiditis (also known as lymphocytic or autoimmune thyroiditis).

3. Myxedema, caused by longstanding untreated hypothyroidism, is a clinical emergency that can be potentially fatal if not treated.

4. Congenital hypothyroidism should be treated as soon as it is suspected to prevent learning disabilities.

Clinical Summary

Thyroid storm, or thyrotoxic crisis, is a life-threatening condition that occurs in individuals with thyrotoxicosis as a result of acute excessive release and/or synthesis of thyroid hormones. The presentation of thyrotoxicosis varies depending on the underlying etiology (eg, Graves disease, subacute thyroiditis, iodide excess, and levothyroxine overdose). Clinical presentation of thyrotoxicosis includes palpitations, anxiety, increased perspiration, fatigue, weight loss, heat intolerance, tremor, and painful goiter (depending on etiology of the thyrotoxicosis). Common signs of thyrotoxicosis include hypertension, tachycardia, muscle weakness, hyperactivity, and eye symptoms such as lid lag and stare. The cardinal presenting features of thyroid storm include fever (almost invariably present; often severe and in excess of temperature elevation expected from the intercurrent illness), tachycardia (out of proportion to the degree of fever), and acute metabolic encephalopathy (extreme restlessness, agitation, psychosis, delirium, confusion, stupor, or coma). Other presenting features include arrhythmias, palpitations, profuse sweating (warm moist skin), heat intolerance, and high-output congestive heart failure (CHF).

Obtain serum thyroid-stimulating hormone (TSH), free T4, T3, and thyroid antibodies (antithyroid peroxidase antibody and thyroid-stimulating immunoglobulins). In thyrotoxicosis, TSH will be suppressed to almost undetectable levels, and free T4 and/or T3 will be elevated. High thyroid-stimulating antibody titers indicate Graves disease. If still not sure of the diagnosis, nuclear thyroid scintigraphy can be done. Obtain electrocardiogram and chest radiograph because of an increased risk of arrhythmias and CHF especially when hypertension, tachycardia, and dyspnea are present. Thymic hyperplasia is often present in children with thyrotoxicosis severe enough to cause tracheal compression. Dyspnea can be present secondary to muscular weakness (and not necessary from cardiac complication or CHF). This is important to differentiate for further management and disposition. A complete blood count, serum electrolytes including calcium and parathyroid hormone levels and liver function tests, should be done at the baseline. Pregnancy test should be obtained for all postmenarchal adolescent females both to rule out rare causes of thyrotoxicosis secondary to extreme elevation of human chorionic gonadotropin levels and pre-radioiodine exposure when needed.

Emergency Department Treatment and Disposition

Patients with thyroid storm require ICU monitoring during the initial phases of therapy. Supportive measures include control of hyperpyrexia with a cooling blanket, ice packs, and acetaminophen (avoid aspirin as it displaces T4 from thyroid-binding protein), treatment of the precipitating event (eg, infection), and reduction of fluid deficits. Initial management with beta-blockers and antithyroid medications should be started immediately. Some endocrinologists recommend steroid use for 3 to 5 days to reduce inflammation and some effects associated with goiter. Methimazole is the first-line treatment except for pregnant patients. Propylthiouracil is used for patients in the first and second trimesters of pregnancy. Patients with thyrotoxicosis generally do not require hospital admission; however, they should be assessed for any complications and, if stable, should be referred to endocrinology.

Pearls

1. The terms hyperthyroidism, thyrotoxicosis, and thyroid storm describe the continuum of disease that results from hyperfunction of the thyroid gland.

2. Thyroid storm may be the initial presentation of thyrotoxicosis in undiagnosed children, particularly in neonates.

3. Thyroid storm is almost invariably fatal if left untreated; therefore, rapid diagnosis and aggressive treatment are critical.

4. Graves disease is the most common cause of thyrotoxicosis and patients usually present with a firm, diffusely enlarged goiter and ophthalmopathy (eg, exophthalmus, periorbital edema, diplopia).

5. Exclude cardiac complications even with mild thyrotoxicosis.