Section F: Endocrinology

BACKGROUND

Insulin is produced by beta cells in the islets of Langerhans in the pancreas. Insulin secretion is regulated by glucose influx into the beta cell, which is dependent on the serum glucose level. Insulin acts on target tissues including liver, fat, and muscle to stimulate glucose uptake and inhibit gluconeogenesis, glycogenolysis, lipolysis, and ketogenesis.

The prevalence of diabetes mellitus in the United States in youth less than 20 years of age is 0.182%.¹ Type 1 diabetes accounts for 85% of these cases, while type 2 diabetes accounts for 12%, and maturity-onset diabetes of the young (MODY) accounts for 1% to 2%. The incidences of type 1 diabetes and type 2 diabetes in children are both increasing, although the United States has seen a particularly striking increase of type 2 diabetes in children and young adults in the past several years.

PATHOPHYSIOLOGY

Hyperglycemia results from abnormal insulin production, abnormal insulin action, or both. In type 1 diabetes, autoimmune destruction of beta cells results in an absolute insulin deficiency. Approximately 90% of patients with type 1 diabetes have measurable serum antibodies against islet cells, glutamic acid decarboxylase (GAD), or insulin.² However, although autoimmunity is an essential component of the pathogenesis of type 1 diabetes, it alone is not sufficient; environmental factors including diet, prenatal influences, infectious exposures, stress, and genetic factors contribute to development of this disease.

Type 2 diabetes is characterized by insulin resistance, often due to obesity, with resulting beta cell dysfunction and glucotoxicity that results in a relative insulin deficiency despite hyperinsulinemia. Although the etiology of type 2 diabetes is multifactorial, there is a stronger genetic component than for type 1 diabetes.²

CLINICAL PRESENTATION

Patients with hyperglycemia often have a history of polyuria, polydipsia, polyphagia, weight loss, and/or fatigue. Depending on the duration of illness and the underlying pathophysiology, the patient may or may not have ketosis or acidosis as a consequence of absolute or relative insulin deficiency. Although more common in type 1 diabetes, ketosis and acidosis can also occur in type 2 diabetes.

Children with newly diagnosed diabetes may present to the hospital in advanced stages of metabolic decompensation because the symptoms of hyperglycemia were not recognized. Treatment of diabetic ketoacidosis (DKA) in childhood requires strict attention to fluid balance and neurologic status because of the increased risk of cerebral edema in the pediatric population. Early detection of diabetes can reduce these risks.

DIFFERENTIAL DIAGNOSIS

The cause of hyperglycemia is not always apparent at initial presentation. The differential diagnosis includes type 1 diabetes, type 2 diabetes, MODY, “stress hyperglycemia” from illness or trauma, pancreatitis, other pancreatic dysfunction (e.g. cystic fibrosis), and drug effect (glucocorticoids, antipsychotics, etc.). Less commonly, hyperglycemia may be seen in the setting of other endocrine disorders such as excess endogenous glucocorticoid, growth hormone, or catecholamine. Type 1 diabetes can also be a component of autoimmune polyendocrine syndrome type 2, which includes autoimmune primary adrenal insufficiency (Addison disease) and autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease).

Patients may experience a period of absolute insulin deficiency at the time of diagnosis and present with ketosis with or without acidosis. Younger age at presentation and Caucasian ethnicity is associated with increased likelihood of type 1 diabetes. Most patients with type 1 diabetes present before the age of 30 years, and for this reason the condition was previously termed “juvenile-onset” diabetes. It is now clear, however, that autoimmune diabetes may develop at any age. Obesity and acanthosis nigricans (thickening and darkening of the skin in flexural areas such as the axillae and posterior of the neck) should raise the possibility that a child has type 2 diabetes, even in the setting of ketoacidosis. These patients typically do not have antibodies against islet cells, GAD, or insulin. This form of diabetes was previously labeled as “adult-onset” diabetes; however, the incidence of type 2 diabetes in the pediatric population is increasing rapidly as childhood obesity has become more prevalent.^1,3

MODY is a relatively rare group of disorders of insulin secretion and glucose disposal. They vary in their severity and presentation, and management often differs from that of type 1 and type 2 diabetes. Each is caused by a single gene mutation and is inherited in an autosomal dominant pattern. Insulin resistance and obesity are not features of these disorders.⁴

DIAGNOSTIC EVALUATION

Criteria for the diagnosis of diabetes include a random plasma glucose ≥200 mg/dL or hemoglobin A1c ≥ 6.5% with symptoms of diabetes, or a fasting (at least 8 hours) plasma glucose ≥126 mg/dL, or a 2-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test using a glucose load of 1.75 grams/kg (up to 75 grams).

If an asymptomatic patient is found to have a fasting plasma glucose ≥126 mg/dL or a random plasma glucose ≥200 mg/dL as part of screening labs, these should be repeated on a second day to confirm these results. However, if a patient with signs and symptoms of diabetes including polyuria, polydipsia, or weight loss is found to have a random glucose of ≥200 mg/dL, no further testing is needed for diagnosis.⁵

HYPERGLYCEMIC STATES

Patients with diabetes can present various hyperglycemic states, each with its own diagnostic criteria and management. The various ways in which diabetes can present are described below; the management will be discussed later.

Hyperglycemia with Ketoacidosis

DKA is defined by a glucose ≥200 mg/dL, venous pH <7.3 or HCO₃ <15 mM, and ketonuria or ketonemia.⁶ Patients presenting with DKA should be admitted to an intensive care unit (ICU) or a medical unit that is prepared to handle a patient requiring close monitoring of vital signs and neurologic status, frequent blood glucose monitoring, and frequent lab draws.

Hyperglycemia with Ketosis and without Acidosis

Diabetic ketosis without acidosis (DK no A) is defined by a glucose ≥200 mg/dL, venous pH ≥7.3 or HCO₃ ≥15 mM, and the presence of ketones in urine or blood. In the patient who has a history of diabetes, it is reasonable to consider emergency department management with a discharge to home if there is a good response to intravenous fluids and insulin. Most centers will admit a patient with new-onset diabetes for initiation of insulin therapy and diabetes education regardless of whether ketones are present or absent (see Management).

Hyperglycemic Hyperosmolar Syndrome

Hyperglycemic hyperosmolar syndrome (HHS), also known as hyperosmolar hyperglycemic nonketotic (HHNK) syndrome, is defined by a glucose >600 mg/dL, serum osmolality >330 mOsm, venous pH >7.3, HCO₃ >15 mM, and absent to small ketonuria or ketonemia. It is often accompanied by hypernatremia, significant dehydration, and altered mental status.^6,7 Admission to an ICU is indicated due to increased risk of cerebral edema and stroke in these patients even in comparison to DKA.

Mixed Hyperglycemic Hyperosmolar State and Ketoacidosis

Mixed hyperglycemic hyperosmolar state and ketoacidosis, defined by glucose >600 mg/dL, serum osmolality >320 mOsm, venous pH <7.3, HCO₃ <15 mM, and moderate or large ketonuria or ketonemia, often with hypernatremia, significant dehydration, and altered mental status,^6,7 warrants admission to an ICU, particularly if there is evidence of altered mental status.

INITIAL ASSESSMENT

The initial assessment of a patient with hyperglycemia includes a physical exam that pays careful attention to vital signs, status of the respiratory, cardiovascular, and neurologic systems, and to hydration status. The patient’s body mass index and the presence or absence of acanthosis nigricans may provide insight into the underlying pathophysiology.

The initial laboratory evaluation of newly diagnosed diabetes should include a venous or arterial blood gas, basic metabolic panel (to evaluate electrolytes, CO₂, BUN, and creatinine), phosphorus, magnesium, insulin, C-peptide, hemoglobin A1c, GAD-65 antibodies, islet cell antibodies, and insulin autoantibodies. Urine should be assessed for the presence of glucose and ketones. In patients with significant electrolyte abnormalities, an electrocardiogram (ECG) should be obtained. If the patient is experiencing altered mental status, a retinal exam and a head CT should be considered to evaluate for cerebral edema.

The history should include the duration of illness, precipitating factors (such as infection, trauma, stress, puberty, or pregnancy), the patient’s previous weight, and any prescription or nonprescription drugs the patient may have taken. If diabetes has previously been diagnosed, it is helpful to know the current insulin regimen, time of the last insulin dose, and the patient’s compliance with treatment. If this is the patient’s first presentation with hyperglycemia, any family history of autoimmune disease, type 1 or 2 diabetes, and gestational diabetes should be elicited. Patients with type 1 diabetes should have inappropriately low insulin and C-peptide levels. Most but not all patients with type 1 diabetes have positive diabetes antibodies. It is not uncommon for patients with type 2 diabetes to also have inappropriately low insulin and C-peptide levels given their blood glucose level, due to beta cell toxicity at the time of initial presentation; however, most patients with type 2 diabetes present with hyperinsulinemia indicative of insulin resistance (Figure 68-1).

MANAGEMENT

Rapid evaluation of the patient should be quickly followed by initiation of treatment. The aim is to reverse the metabolic disturbance and restore and maintain intravascular volume. However, fluid and insulin management must be titrated carefully because rapid changes in glucose and osmolality may contribute to the development of complications.⁸

TREATMENT OF DIABETIC KETOACIDOSIS

This section is not intended as a rigid protocol but is offered as a guideline. DKA management is dynamic and each case should be assessed individually and reassessed frequently during the course of treatment.

Fluids

Emergency fluid resuscitation is determined by assessment of the patient’s hydration status (perfusion, heart rate, and blood pressure). A bolus of 10 to 20 mL/kg of normal saline (NS) over a 1-hour period is typically used in a mildly to moderately dehydrated patient (keep in mind that the degree of dehydration is often underestimated). The bolus can be repeated if necessary, and clinical status and medical history will dictate whether a conservative or aggressive approach to fluid management is warranted (e.g. history of congestive heart failure or evidence of hypovolemic shock, respectively). Following this acute management, the fluid deficit should be replaced evenly over a minimum of 48 hours, in addition to maintenance fluids. The patient’s ongoing losses must also be monitored, and if excessive, these losses may require replacement as well. Fluid management must be reassessed at a minimum of every 4 hours. Inadequate hydration will contribute to persistent acidosis. Prolonged administration of hypertonic fluids can result in hyperchloremic metabolic acidosis. Slower fluid replacement should be considered in a patient who is very young, has had a prolonged prodrome, has severe acidosis, has an elevated corrected sodium, or has significantly elevated serum osmolality (>300 mOsm). (see Box 68.1). The patient in DKA should remain without oral intake during the initial stabilization due to potential risk of decompensation.

Maintenance fluids can be given as NS when in DKA; this can be transitioned to ½ NS once the acidosis has resolved. However, the sodium content of the fluid may need to be adjusted, depending on the patient’s age, serum osmolality, and serum electrolytes. If serum osmolality is <300 mOsm, aim to replace the deficit over a 48-hour period. If serum osmolality is ≥300 mOsm or dehydration is >10%, aim to replace the deficit over a 48-hour period or longer. NS should be used for replacement fluids. The volume of the initial resuscitation fluid should be subtracted from the total deficit when calculating the volume that should be replaced over the following 48 hours. Ongoing fluid losses are not generally replaced unless they are excessive (urine output >4 mL/kg/hr); such losses include urine, vomiting, and Kussmaul respirations.

Potassium

Total body potassium is depleted in DKA and should be added to the intravenous fluids as soon as the following criteria have been met: serum potassium is <6.0 mEq/L, the patient has voided, and the ECG demonstrates an absence of peaked T waves. Because potassium will be driven back into cells as the acidosis resolves, timely addition of potassium will help avoid the development of life-threatening arrhythmias that can occur if hypokalemia develops with correction of the acidosis. Potassium can be added to fluids in the form of potassium phosphate and potassium chloride.

Phosphorus

Total body phosphorus is also depleted in patients who present with DKA. However, symptomatic hypophosphatemia is extremely rare, and intravenous replacement of phosphorus is controversial. Phosphate supplementation may be considered if there has been a prolonged period of illness or if an extended period of fasting is anticipated. Potassium phosphate can be used along with potassium chloride in this instance to provide both potassium and phosphorus intravenously. The major risk with phosphate administration is the development of hypocalcemia and arrhythmia. Calcium levels must be monitored carefully, and if hypocalcemia develops, the phosphate infusion should be discontinued immediately. Hypocalcemia may be challenging to correct in the unusual setting of concurrent untreated hypomagnesemia.

Bicarbonate

DKA is the result of increased ketogenesis due to insulin deficiency and should reverse with insulin therapy. Administration of bicarbonate is not recommended in the management of DKA and should be undertaken with extreme caution when being considered.^6,8,9 Bicarbonate may be appropriate in certain situations, but it is important to consider that there is evidence that sudden correction of blood pH can paradoxically lower cerebrospinal fluid pH. Moreover, bicarbonate administration has been shown to be an independent risk factor for cerebral edema. It is important to recognize that endogenous production of bicarbonate will occur as ketones are metabolized once insulin is administered. As a result, the usual calculation used for the correction of acidosis will overestimate the bicarbonate required to correct acidosis in patients with DKA. The effect of bicarbonate administration on serum potassium must also be considered, and additional potassium administration may be required.

Insulin

Although differentiating between type 1 and type 2 diabetes is important for long term therapy and education, any patient with fasting hyperglycemia, ketosis, and metabolic abnormalities requires insulin therapy to reverse these derangements.⁵ Administration of insulin via an intravenous drip allows for rapid insulin action and dose adjustment. Ideally, an insulin infusion should be initiated within the first 2 hours of treatment of DKA. The initial insulin infusion rate should be 0.1 units/kg/hour. To ensure good flow of insulin into the patient, it is recommend to mix insulin with NS at a concentration of 0.1 units/mL (50 units of regular insulin in 500 mL of 0.9% NS). The insulin infusion must be regulated with a pump and should be included when calculating total fluids.

The response to insulin therapy is ultimately measured by resolution of ketosis and a rise in the serum bicarbonate level. The insulin infusion rate should be maintained until the ketosis has markedly improved or resolved. Since insulin will lower blood sugar before resolution of the ketosis and acidosis, dextrose will need to be added to the intravenous fluids at some point to avoid a rapid decline in serum glucose or frank hypoglycemia, or both. Generally, dextrose is added to the fluids when serum glucose levels fall below 300 mg/dL, but in certain circumstances dextrose may need to be added earlier (see below).

After initial fluid management and initiation of insulin therapy, the goal should be to decrease blood glucose by 50 to 100 mg/dL/hr. A larger decrease may be seen with initial fluid resuscitation, depending on the patient’s hydration status. The goal is to maintain the corrected serum sodium and to see an increase in the measured serum sodium as the blood glucose level falls. If marked hyperosmolality is present (glucose >1200 mg/dL, serum osmolality >300 mOsm), the therapeutic goals should be adjusted to replace the fluid deficit over a period of 48 to 72 hours, and after an initial period of rehydration, to lower the blood glucose by 50 mg/dL/hr.

Continued Monitoring and Reevaluation

After initial therapy for DKA has been instituted, monitor blood pH and electrolytes every 1 to 2 hours until the patient is improving (pH >7.3 or bicarbonate >15 mM) and then every 2 to 4 hours. Check serum glucose levels every hour via finger stick (or laboratory glucose if too high for the glucose monitor). Neurologic status should be evaluated every 1 to 2 hours. Urine output should be recorded and overall input and output reviewed frequently. A flow sheet is extremely helpful to track changes in fluid balance, vital signs, electrolytes, urine ketones, and blood sugar. It is important to note that serum ketones and urine ketones may not exactly coincide; however, urine ketones are often used to track improvement in DKA.⁶

Complications

Complications associated with DKA resuscitation include hypoglycemia, hypokalemia, hypophosphatemia, hypocalcemia, hypernatremia, fluid overload with edema, acute respiratory distress syndrome, and symptomatic cerebral edema.

Cerebral edema is the leading cause of death in DKA with a mortality rate of 21% to 24%. The incidence of cerebral edema is generally reported as less than 1%.⁶ Patients at particularly high risk include those younger than 5 years of age and those with severe acidosis, severe dehydration, and high serum osmolarity.⁹ Symptoms of cerebral edema include any change in sensorium, headache, increased drowsiness, deepening coma, and cranial nerve abnormalities. Cushing’s triad (increased blood pressure, decreased heart rate, irregular respirations) may be seen in the setting of increased intracranial pressure, which is a neurosurgical emergency. It is important to have mannitol or hypertonic saline available when a patient is admitted with DKA in the event that symptomatic cerebral edema develops. Case reports have shown possible beneficial effects of mannitol or hypertonic saline. Intravenous mannitol should be given (0.25–0.5g/kg over 20 minutes) in patients with signs of cerebral edema and impending respiratory failure. If there is no initial response, it should be repeated in 2 hours. Hypertonic saline (3%) (5 mL/kg over 30 minutes), may be a reasonable alternative to mannitol if there is concern for hypotension (and cerebral hypoperfusion) due to an osmotic diuresis that could be seen with mannitol administration. Intubation and ventilation may be necessary in severe DKA. Mild hypercapnea, however, should be tolerated, as aggressive hyperventilation has been associated with poor outcomes in DKA-related cerebral edema.⁶

Transition to Subcutaneous Insulin

The criteria for switching from an intravenous insulin infusion to subcutaneous insulin injections include the ability to tolerate oral intake, a normal mental status, and resolved acidosis (bicarbonate ≥15 mM or pH ≥7.3). The first dose of subcutaneous insulin should be given 15 to 60 minutes (15–30 minutes with rapid acting, 30–60 minutes with regular insulin) before stopping the intravenous infusion to allow sufficient time for absorption. It is optimal to convert to a subcutaneous regimen just before a meal. For patients in DKA, it is convenient, when possible, to give long-acting basal insulin while still on infusions in order to help with the transition to subcutaneous insulin. A typical starting daily dose of insulin for a patient with type 1 diabetes is between 0.4 and 1 units/kg/day, but the dose and type of subcutaneous insulin varies by institution and should be taken into consideration when planning a regimen (Table 68-1). Treatment needs to be individualized for each patient and should be discussed with a pediatric endocrinologist. Patients with previously diagnosed diabetes can usually be started on their home insulin regimen.

Patients with a new diagnosis of type 2 diabetes who present with a hemoglobin A1c of ≥8.5% will likely be initiated on insulin therapy and require initial insulin doses of at least 1 unit/kg/day, as they will demonstrate mild to severe insulin resistance. Metformin can also be used in patients 10 years of age and older, provided they do not have significant kidney or liver dysfunction. This medication improves insulin sensitivity, which should, over time, decrease their insulin requirement.

TREATMENT OF THE HYPERGLYCEMIC HYPEROSMOLAR STATE

A hyperglycemic hyperosmolar state may be seen in type 1 diabetes, although it is more common in type 2 diabetes. Management of this disorder is outside the scope of this chapter and should involve the ICU team. It is important to know, however, that the underlying pathophysiology involves severe dehydration and requires that adequate fluid administration precede insulin administration to avoid cardiovascular collapse.⁸

TREATMENT OF HYPERGLYCEMIA WITHOUT ACIDOSIS

If the initial workup reveals only hyperglycemia or hyperglycemia with mild to moderate ketosis, it may be possible to manage the patient with oral rehydration and subcutaneous insulin therapy. This approach is not appropriate in patients with hyperosmolality, nausea or vomiting, or another issue precluding oral intake. Electrolyte imbalance is less frequently seen and can usually be corrected with oral therapy. The approach to insulin management is similar to that described in the previous section.

ADMISSION AND DISCHARGE CRITERIA

ADMISSION CRITERIA

• Hyperglycemia accompanied by ketosis and acidosis

• Altered mental status

• Any patient receiving insulin who is unable to tolerate sufficient oral intake to prevent hypoglycemia and dehydration

• Pediatric patients with newly diagnosed diabetes requiring initiation of insulin therapy if intensive education is not immediately available on an outpatient basis

DISCHARGE CRITERIA

• Normal electrolytes and hydration status

• Ability to tolerate oral intake

• It is not necessary to obtain perfect glucose control before discharge; insulin doses will require adjustments after discharge and on an ongoing basis

• For a patient being discharged on insulin therapy, it is necessary to ensure that the family has been educated regarding the following:

  • Definition and pathophysiology of the different types of diabetes

  • Insulin action

  • Signs and symptoms of hypoglycemia

  • Treatment of hypoglycemia and use of glucagon

  • Proper technique in using the glucometer

  • Proper technique in drawing up and administering insulin

  • Consequences of poor glycemic control

  • Follow-up should be arranged with a pediatric endocrinologist as an outpatient

CONSULTATIONS

• Pediatric endocrinology

  • Possible: pediatric critical care, pediatric neurosurgery

SPECIAL CONSIDERATIONS

COMORBIDITIES

Patients with type 1 diabetes are at increased risk for other autoimmune disorders such as hypothyroidism and celiac disease. Patients with type 2 diabetes are at increased risk for non-alcoholic steatohepatitis and dyslipidemia. Patients with known diabetes should have screening for these comorbidities, in addition to assessment of urine microalbumin to detect nephropathy and ophthalmology exam to detect retinopathy.

PREVENTION

Prevention of type 1 diabetes is currently being studied at three levels. Primary prevention aims to prevent development of autoantibodies that could lead to type 1 diabetes by means of diet modifications and antigen-specific vaccines. Secondary prevention aims to prevent beta cell destruction in patients who already have developed autoantibodies. Tertiary prevention aims to preserve beta cell function in patients already diagnosed with type 1 diabetes via immunomodulators.¹⁰

Prevention of type 2 diabetes involves lifestyle modifications such as dietary alterations and increased exercise to induce weight loss. Bariatric surgery can also prevent progression of and reverse metabolic syndrome and type 2 diabetes, although such procedures are controversial in children.¹¹

NEW THERAPIES

Several new drugs are approved for use in adults with type 2 diabetes that may prove beneficial to the pediatric population as well. First are the injectable agents (exenatide and liraglutide), which are modeled after the human incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 is secreted in response to food intake and has multiple effects on the stomach, liver, pancreas, and brain. The next new class of drugs for treatment of type 2 diabetes are inhibitors of dipeptidyl-peptidase-4 (DPP-4), the enzyme that inactivates GLP-1. Third, pramlintide, a synthetic amylin analogue, has been shown to decrease glucagon secretion and delay gastric emptying, resulting in less glycemic excursion and facilitating weight reduction without causing hypoglycemia.¹¹

Investigational therapies for type 1 diabetes include closed-loop insulin delivery systems, immunomodulators, improved islet transplantation techniques, and stem cell differentiation.¹⁰

REFERENCES

BACKGROUND

Thyroid hormone has many effects on the human body. It plays an essential role in growth and development, thermogenesis, oxygen consumption, and the metabolism of carbohydrates, lipids, and proteins. Although thyroid hormone is essential for the normal function of many tissues, thyroid dysfunction is frequently insidious and may be missed.

The hypothalamic-pituitary-thyroid axis is finely tuned to maintain stable levels of thyroid hormone in the body. Thyrotropin-releasing hormone (TRH) is produced in the hypothalamus and stimulates the production and secretion of thyroid-stimulating hormone (TSH) by the anterior pituitary gland.¹ Through binding of the thyroid-stimulating hormone receptor (TSHR), TSH leads to production and release of the thyroid hormones, thyroxine (T4) and triiodothyroxine (T3), as well as thyroid cell growth. Thyroid hormones feedback on the anterior pituitary and hypothalamus, decreasing secretion of TSH and TRH, respectively, allowing for tight regulation of thyroid hormone concentrations. The predominant form of hormone secreted by the thyroid is T4, which then undergoes peripheral conversion to T3 by types I and III deiodinases. T3, the metabolically active hormone, and exerts its effects by binding nuclear receptors and influencing DNA transcription. T4 may also be converted into the inactive reverse T3 (rT3) by deiodinase type III. Increased rT3 is commonly seen in the fetus and in severely ill patients.¹

The majority of thyroid hormone circulates bound to thyroid-binding globulin (TBG) and to a lesser extent, other serum proteins. The remainder circulates unbound (free) and is metabolically active. Estrogen decreases TBG clearance, leading to higher levels of total thyroid hormone. As a result, oral contraceptive pill use or pregnancy will lead to elevated total T4 levels, but the free amount of thyroid hormone remains normal.

The maturity level of the hypothalamic-pituitary-thyroid axis must be considered to correctly interpret thyroid function tests in newborns and children. At birth, an acute surge in TSH occurs in response to exposure to the cold extrauterine environment, resulting in a rise in T4 and T3 levels. TSH remains elevated for 3 to 5 days after birth while the T4 and T3 levels gradually decline over the first 2 to 4 weeks of life.² During childhood, there is a progressive decrease in TSH and thyroid hormone levels until approximately age 15 to 16 years, when adult levels are reached (Table 69-1).

CLINICAL PRESENTATION

HYPOTHYROIDISM

Congenital Hypothyroidism

Congenital hypothyroidism, defined as thyroid hormone deficiency present at birth, occurs in approximately 1:2000 to 1:4000 newborns and is one of the leading causes of preventable intellectual disability.² The clinical manifestations are often subtle and usually not present at birth. Symptoms include lethargy, difficulty feeding, constipation, a hoarse cry, and prolonged jaundice. Physical examination may show a wide posterior fontanel, macroglossia, coarse facies, umbilical hernia, and hypotonia. Placental transfer of maternal thyroid hormone protects the developing fetus.³ Due to newborn screening, infants are usually identified before they develop clinical signs or symptoms of hypothyroidism.

Acquired Hypothyroidism

Hashimoto thyroiditis or autoimmune hypothyroidism is the most common cause of acquired hypothyroidism in children. The presentation is variable as the child may be euthyroid, hypothyroid, or transiently hyperthyroid at diagnosis. Children may complain of neck swelling, fatigue, constipation, cold intolerance, and in pubertal girls, menstrual irregularities. 70% to 80% of children with hypothyroidism will present with a goiter, which is typically symmetric and nontender.⁴ Other exam findings include bradycardia, proximal muscle weakness, delayed deep tendon reflexes, and growth failure (Figure 69-1). Hypothyroidism produces poor linear growth with preservation of normal weight gain, and these children may be relatively overweight for their height, but contrary to popular belief, hypothyroidism generally does not cause obesity.

Autoimmune hypothyroidism has a female predominance (2:1) and 40% to 50% of patients will have a positive family history of autoimmune thyroid disease.⁴ It can be associated with other autoimmune disorders, including type 1 diabetes mellitus, primary adrenal insufficiency (Addison disease), and celiac disease. Autoimmune thyroiditis is also more common in patients with certain chromosomal disorders, such as Down syndrome and Turner syndrome.

HYPERTHYROIDISM

Neonatal Hyperthyroidism

Neonatal thyrotoxicosis (neonatal Graves disease) is a rare disorder, occurring in only 1% to 1.4% of pregnancies affected by maternal Graves disease (autoimmune hyperthyroidism).⁵ It is most commonly due to transplacental passage of TSH receptor-stimulating antibodies from a mother with Graves disease, leading to increased thyroid hormone production in the fetus. The hyperthyroidism persists until the maternal antibodies are cleared from the infant’s circulation, which can take up to 3 to 4 months. Thyrotoxicosis may be suspected due to fetal tachycardia and intrauterine growth restriction. Clinical symptoms in the neonate are variable and may not occur until several days after birth due to antithyroid medications taken by the mother during pregnancy. Neonates may present with irritability, tachycardia, jaundice, poor weight gain, and exophthalmos.⁵ Affected infants need to be admitted to a neonatal intensive care unit for close monitoring of vital signs and frequent testing of thyroid labs, as neonatal hyperthyroidism can result in high-output cardiac failure and even death. A pediatric endocrinologist should be consulted immediately if neonatal hyperthyroidism is suspected. Untreated infants that survive may develop advanced bone age, craniosynostosis, and intellectual disability.

Graves Disease

The most common cause of hyperthyroidism in children is Graves disease (autoimmune hyperthyroidism), occurring in 1:10,000 children in the United States.⁶ There is a female predominance and peak incidence is during adolescence. Graves disease is an autoimmune disorder in which antibodies against the TSH receptor (also known as thyroid-stimulating immunoglobulins) cause the overproduction and secretion of thyroid hormone. The symptoms are often insidious and the rarity of the disorder and its nonspecific symptoms often result in a delay in diagnosis. Children may present with fatigue, weight loss, palpitations, increased bowel movements, irritability, and difficulty sleeping. Parents may report that their child has deteriorating school performance and decreased concentration.⁶ On examination, the thyroid is generally diffusely enlarged, and the patient may have tachycardia, hypertension, hyperreflexia, and a fine tremor. Ophthalmopathy (thyroid eye disease) may occur in children, but less commonly than in adults.

Thyroid storm in children is extremely rare, but is a medical emergency. It consists of acute hyperthermia, tachycardia, and encephalopathy in a patient with hyperthyroidism. Heart failure can result from the tachycardia. Thyroid storm may be precipitated by infection, surgery, or noncompliance with antithyroid medications.

DIFFERENTIAL DIAGNOSIS

HYPOTHYROIDISM

Congenital Hypothyroidism

Congenital hypothyroidism can be permanent or transient and is classified as primary, due to an inherent defect of the thyroid gland or thyroid hormone production or secretion, or secondary (central), due to defects in the pituitary/hypothalamus. Eighty-five percent of primary congenital hypothyroidism is caused by thyroid gland dysgenesis.² The gland may be ectopically located, hypoplastic, or absent. In some parts of the world, iodine deficiency is an important cause of congenital hypothyroidism; however, this condition is almost nonexistent in the United States. Isolated TSH deficiency is very rare and central congenital hypothyroidism occurs more commonly in the presence of other pituitary deficits. The presence of midline defects, micropenis, and/or hypoglycemia in a neonate suggests the possibility of hypopituitarism, which could be due to anatomical defects of the pituitary or septo-optic dysplasia, a disorder in which pituitary deficiencies may also occur later in life.

Transient congenital hypothyroidism is rare, but can be caused antithyroid medications taken by the mother during pregnancy that cross the placenta, inhibiting fetal thyroid hormone production. Generally, neonatal hypothyroidism induced by maternal medication resolves within 1 to 2 weeks. Other causes of transient congenital hypothyroidism include iodine deficiency or excess in the mother, pre- or postnatal exposure to iodine, and maternal TSH receptor-blocking antibodies that cross the placenta and block thyroid hormone production in the fetus/neonate.²

Acquired Hypothyroidism

Acquired hypothyroidism is also classified as primary or secondary. Hashimoto, or autoimmune, hypothyroidism, is the most common cause of primary acquired hypothyroidism. Other causes include radiation to the neck, commonly used in the treatment of certain types of lymphoma, and surgical resection of the thyroid gland for treatment of Graves disease or thyroid cancer. Certain medications can also induce hypothyroidism.⁷ Drugs that down-regulate the release of TSH from the pituitary include glucocorticoids and dopamine. Glucocorticoids also appear to inhibit the peripheral conversion of T4 to T3. Drugs that affect thyroid hormone synthesis and release include amiodarone and iodine, and lithium. Although iodine is essential for proper thyroid function, large amounts can block the release of preformed thyroid hormone and the synthesis of new hormone (the Wolff–Chaikoff effect). Hypothyroidism is seen in infants or children who receive large amounts of cutaneous iodine for surgical procedures or those receiving amiodarone, which contains significant amounts of iodine. Lithium carbonate, used to treat psychiatric disorders, inhibits thyroid hormone release. Antiepileptic medications, particularly phenytoin and carbamazepine, increase hepatic metabolism of thyroxine, which can result in low levels of total T4 with normal TSH and T3 levels.

Central hypothyroidism should be suspected in children with a history of central nervous system disease, such as hydrocephalus, hemorrhage, brain tumor, or meningitis, or central nervous system malformations. In any patient with central hypothyroidism, it is important that other pituitary hormone deficiencies be investigated, such as deficiencies of adrenocorticotropic hormone, growth hormone, gonadotropins, and vasopressin.

Nonthyroidal illness (NTI), also known as sick euthyroid syndrome, is seen in severely ill patients and in states of starvation.¹ Patients will commonly have low or normal TSH, low total T4 and T3, and normal or high free T4 levels. Multiple mechanisms may give rise to these changes, including suppression of TSH secretion by cytokines and decreased peripheral conversion of T4 to T3.⁸ Reverse T3 (rT3) levels are generally elevated, because conversion of T4 to rT3 is not impaired, and the degradation of rT3 is reduced. NTI is thought to be a protective adaptive response aimed at decreasing metabolism and preserving energy stores during stress. There is no clear evidence that treatment of NTI with thyroid hormone replacement improves outcomes.

HYPERTHYROIDISM

In addition to Graves disease, other causes of hyperthyroidism in childhood and adolescence include autonomously functioning thyroid nodules, infections of the thyroid. and McCune–Albright syndrome. Hashimoto thyroiditis may have a hyperthyroid phase during destruction of the thyroid gland resulting in release of pre-formed thyroid hormone and transient hyperthyroidism. Drugs that can cause hyperthyroidism include amiodarone, iodine, and intentional or accidental ingestion of levothyroxine.⁵

DIAGNOSTIC EVALUATION

HYPOTHYROIDISM

An elevated serum TSH in the presence of low T4 levels is consistent with primary hypothyroidism. In subclinical primary hypothyroidism, there will be a mildly elevated TSH with normal T4 levels. In contrast, a child with central hypothyroidism can have a low, normal, or even elevated TSH combined with low T4 levels.

Congenital Hypothyroidism

The vast majority of infants with congenital hypothyroidism are identified through newborn screening programs in countries with such programs. The newborn screen is based on the measurement of T4 or TSH (or both) in a dried blood filter paper sample obtained between 2 and 4 days of life (or at discharge from the hospital).³ There are advantages and disadvantages to either a T4 or TSH screening approach. If T4 is measured, infants with a T4 level below a specific cutoff point have their TSH measured as well. This method can miss subclinical hypothyroidism (normal T4 but elevated TSH levels). Primary screening with TSH has a higher false-positive rate owing to the early screening (before 2 days of life) and it also misses infants with central hypothyroidism.

When the newborn screen reports abnormal thyroid tests, the infant should be seen and examined immediately and serum confirmatory testing should be obtained. The newborn screen should not be repeated for confirmation as that can result in delayed treatment.³ Thyroid function testing should include TSH and free T4 or total T4 combined with a measure of binding proteins, such as a T3 resin uptake. Once the diagnosis of hypothyroidism is confirmed, additional diagnostic tests can be performed in order to determine its etiology. A technetium scan can establish whether there is any thyroid tissue or an ectopic or hypoplastic thyroid. A scan with normal uptake suggests dyshormonogenesis. Obtaining the technetium scan should not delay the initiation of treatment, because the scan can still be performed within the first several days of levothyroxine therapy. A thyroid ultrasound study is noninvasive and is easier to obtain, but is generally not as accurate the technetium scan in detecting an ectopic gland. Controversy exists as to whether or not these additional tests are necessary in the diagnosis of congenital hypothyroidism, and the American Academy of Pediatric guidelines classify them as optional.³

Low thyroid hormone in the setting of a low or normal TSH level is suggestive of central hypothyroidism and hypopituitarism. An infant with this presentation should be monitored carefully for hypoglycemia and must undergo evaluation of the other pituitary hormones. It is particularly crucial to identify if there is central adrenal insufficiency, and if detected, cortisol must be adequately replaced prior to initiating thyroid hormone replacement. Thyroid hormone supplementation increases cortisol clearance from the circulation and could precipitate cardiovascular collapse and adrenal crisis in patients with adrenal insufficiency.

Acquired Hypothyroidism

Evaluation of older children with suspected acquired hypothyroidism should include a serum TSH with a total and free T4. Antithyroid peroxidase and antithyroglobulin antibodies can be obtained to confirm the diagnosis of autoimmune hypothyroidism. Thyroid imaging in acquired hypothyroidism is not usually warranted unless a nodule is present. Low total T4 levels with a normal TSH can be seen with familial thyroid-binding globulin deficiency, an X-linked recessive condition.⁷ The free T4 level should be normal in TBG deficiency, and treatment is not indicated. Children with the diagnosis of acquired central hypothyroidism must have assessment of the other pituitary hormones and require an MRI of the brain and pituitary to rule out a mass.

HYPERTHYROIDISM

Low TSH and elevated T4 and T3 levels are consistent with primary hyperthyroidism. The initial laboratory tests should include serum TSH, free or total T4, and total T3 levels. Measurements of thyroid-stimulating immunoglobulins and TSH receptor antibodies should be obtained to confirm the diagnosis of Graves disease. An I-123 scan may be necessary to distinguish Hashimoto thyroiditis from Graves, given overlap in the antibody profiles.⁶ Hashimoto thyroiditis and Graves can also be distinguished clinically if exophthalmos is present (seen in Graves). In the setting of Graves disease, imaging of the thyroid gland is generally not indicated. However, if a nodule is present or there is an asymmetric gland, a thyroid ultrasound should be obtained.

MANAGEMENT

HYPOTHYROIDISM

Congenital Hypothyroidism

The goal of treatment for congenital hypothyroidism is to adequately replace thyroid hormone as early as possible to maximize the chances for normal neurologic development. Neurodevelopmental outcomes are inversely related to age at diagnosis and start of treatment. Levothyroxine (T4) is the accepted treatment. The starting dose is generally 10 to 15 μg/kg (usually 37.5–50 μg/day) in one daily dose.² However, it has been shown that term infants receiving a dose of 50 μg/day had better neurologic outcomes compared to those receiving 37.5 μg/day.⁹ The goal of treatment is to normalize the T4 level as quickly as possible, recognizing that the TSH will take longer to normalize. Overtreatment with levothyroxine can lead to advanced bone age and craniosynostosis. For infants with a late diagnosis of congenital hypothyroidism who have been hypothyroid for 2 to 3 months, it is advisable to work up to a full replacement dose over 1 to 2 weeks to avoid precipitating rapid mobilization of fluid.

Levothyroxine should be given as a crushed tablet in a small amount of formula, breast milk, or water. Liquid preparations and suspensions of levothyroxine should be avoided, because they are unstable and do not provide reliable dosing. During the first three years of life, the T4 level should be kept in the upper half of the reference range. The AAP recommends clinical and biochemical monitoring at 2 to 4 weeks following levothyroxine initiation; every 1 to 2 months during the first 6 months of life; every 3 to 4 months between 6 months and 3 years old; then every 6 to 12 months until completion of growth.² Given the risk of neurologic damage, careful and ongoing counseling of the parents is essential to limit noncompliance, which is the most common cause of an elevated TSH while receiving treatment.

Acquired Hypothyroidism

The treatment for primary or central acquired hypothyroidism is levothyroxine, which is dosed based on weight and age (Table 69-2). As with congenital hypothyroidism, suspensions of levothyroxine should be avoided. For younger children, tablets may be crushed and mixed with a small amount of liquid or food. Although absorption of levothyroxine is greatest on an empty stomach, dosing at a mealtime is often easiest for families. Any decrease in absorption that comes from taking it with a meal can be compensated with a higher dose. Iron, calcium supplements, and soy products decrease the absorption of levothyroxine and should be administered at a different time.

The goal of treatment is to keep the TSH and T4 within the normal range. Elevated TSH and T4 levels in a patient treated for primary hypothyroidism should raise the suspicion for noncompliance with a recent effort to conceal their noncompliance by taking multiple doses at one time. T4 is monitored in patients with central hypothyroidism.

Treatment of subclinical hypothyroidism and NTI remains controversial. In patients with subclinical hypothyroidism, many practitioners treat with levothyroxine when the TSH rises above 10 mIU/L. There is no evidence to support the treatment of NTI in children and adolescents and it should not be done unless under the guidance of a pediatric endocrinologist.

HYPERTHYROIDISM

Neonatal Hyperthyroidism

Given the risk of cardiac failure and death, treatment for neonatal thyrotoxicosis should be initiated as soon as possible. The antithyroid medications methimazole and propylthiouracil (PTU) block the production of thyroid hormone.⁵ PTU (5 to 10 mg/kg/day) has the additional benefit of blocking the conversion of T4 to T3 and is available in a liquid preparation. However, given the association of PTU and severe liver failure, methimazole (0.5–1 mg/kg/day) is now the first-line agent for treatment of neonatal hyperthyroidism. PTU may need to be used if a compounded suspension of methimazole cannot be obtained. Propranolol (1–2 mg/kg/day) should be administered to treat tachycardia. In severe cases, a saturated potassium iodide solution (SSKI 1 drop/day) or Lugol iodide solution (1–3 drops/day) may be used to decrease thyroid hormone production.⁵ Frequent monitoring of thyroid levels is essential. As the TSH receptor-stimulating antibodies are cleared from the infant’s circulation, the antithyroid medications and propranolol can be weaned and are typically discontinued after 3 to 4 months once the TSI is no longer detectable.

Graves Disease

The first-line treatment for Graves disease in children and adolescents is antithyroid drug therapy with methimazole (0.5 to 1 mg/kg/day or 15–20 mg/day).⁶ As with neonatal Graves disease, use of PTU (5 to 10 mg/kg/day) is now generally avoided due to the association with liver failure. These medications inhibit thyroid hormone formation but not its release, so it may take a number of weeks until circulating thyroid hormone levels begin to decrease. A beta-blocker such as propranolol (1–2 mg/kg/day) or atenolol (0.5–1.2 mg/kg/day) may be added to control tachycardia and ameliorate symptoms while the antithyroid medications take effect. Thyroid levels, including TSH, T4, and T3, should be checked 4 to 6 weeks after starting therapy, then every 2 to 3 months once on a stable dose.⁶ Severe side effects of methimazole include agranulocytosis, hepatitis, and Stevens–Johnson syndrome. Routine monitoring of complete blood cell counts and liver function tests are generally not indicated. Children with ophthalmyopathy should be referred to a pediatric ophthalmologist.

Remission rates for Graves disease are lower in children (30%) than in adults (50%).⁶ Given the difficulty of maintaining compliance and the risk of side effects from antithyroid drug therapy, definitive therapy can be pursued if remission is not achieved within 12 to 24 months or sooner if methimazole cannot be tolerated. With the goal of inducing a hypothyroid state, definitive therapy consists of either radioiodine ablation or surgical removal of the thyroid gland. Radioiodine ablation is a safe and effective treatment in children, with long-term studies showing no evidence of decreased fertility or increase rates of malignancy. Thyroidectomy is generally recommended for younger children (< 10 years), those with large glands, or those with severe eye disease.⁶

Treatment of thyroid storm may include propranolol (2 to 3 mg/kg per day, divided every 6 hours) to control the tachycardia, dexamethasone (1 to 2 mg every 6 hours) to reduce conversion of T4 to T3, and intravenous sodium iodide (125 to 250 mg/day) or Lugol solution (concentrated iodide; 5 drops by mouth every 8 hours) to decrease the release of thyroid hormone from the thyroid gland. Methimazole (0.6 to 0.7 mg/kg per day) or PTU (6 to 10 mg/kg per day; maximum 200 to 300 mg/day) should be started, although the effect will not be seen for several days.

ADMISSION AND DISCHARGE CRITERIA

ADMISSION CRITERIA

• Neonatal thyrotoxicosis

• Thyroid storm

• Congenital hypothyroidism or severe hypothyroidism in an older child if there is any suspicion that the family is not administering the medication properly

DISCHARGE CRITERIA

• Resolution of acute symptoms of neonatal thyrotoxicosis or thyroid storm and improving thyroid function tests on medication.

• For any child with thyroid disease, the family must understand proper dosing and administration of medication, and thyroid function tests should be improving.

CONSULTATION

Most often, thyroid disorders are diagnosed and managed in the outpatient setting. However, if thyroid function tests are obtained on a hospitalized patient, a pediatric endocrinologist should be consulted to interpret the results, because interpretation of such tests obtained during periods of illness can be challenging. A pediatric endocrinologist should always be consulted for patients with possible thyroid storm or infants with suspected neonatal thyrotoxicosis.

SPECIAL CONSIDERATIONS

PREVENTION

Congenital hypothyroidism is a preventable cause of intellectual disability, with earlier recognition and treatment initiation leading to better neurologic outcomes. Therefore it is essential that infants have timely follow-up of their newborn screens and rapid referral for evaluation if their screens are positive for thyroid dysfunction.

REFERENCES

BACKGROUND

The pituitary gland is comprised of two parts with distinct origins. The anterior pituitary is derived embryonically from Rathke’s pouch of oral ectoderm, while the posterior pituitary is of neuroectoderm origin. The pituitary gland regulates endocrine target organs, such as the adrenal gland, ovary, testis, and thyroid gland. Disorders of the pituitary and hypothalamus may therefore result in disruption of any of these hypothalamic-pituitary–target organ axes. Abnormalities in end-organ hormone release caused by pituitary dysfunction are considered “secondary,” and those caused by a hypothalamic abnormality are considered “tertiary.” For example, abnormal thyroid function caused by a decrease in pituitary thyroid stimulated hormone is considered “secondary hypothyroidism” while hypothyroidism due to deficient thyrotropin-releasing factor from the hypothalamus is “tertiary hypothyroidism.” Failure of growth and failure of sexual maturation are two common presentations of hypothalamic-pituitary disease in the pediatric population. Pituitary disorders may be genetic or acquired.

The hypothalamus secretes releasing factors that travel via the portal circulation to the anterior pituitary gland and include growth-hormone releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), and gonadotropin releasing hormone (GnRH). These factors stimulate or inhibit release of the six peptide hormones produced by the five distinct cell types of the anterior pituitary gland: growth hormone (GH) from somatotropes, prolactin by lactotropes, thyroid-stimulating hormone (TSH) from the thyrotropes, adrenocorticotropic hormone (ACTH) via corticotropes, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH), secreted by gonadotropes.

The posterior pituitary gland releases arginine vasopressin, also known as antidiuretic hormone (ADH), and oxytocin. The neurons that produce vasopressin originate in the paraventricular and supraoptic nuclei of the hypothalamus. For this reason, diabetes insipidus (DI) can occur with hypothalamic disease, but may not always occur with pituitary disease, even if the stalk has been transected (depending on the level of transection).

CLINICAL PRESENTATION

GENETIC CAUSES OF PITUITARY HORMONE DEFICIENCY

Several genetic causes of multiple pituitary hormone deficiency have been described (see online eTable 70-1), including mutations in transcription factors integral to the embryonic development of the pituitary. However, known genetic defects still explain less than 20% of hypopituitarism in humans. Congenital malformations involving the midline of the central nervous system (CNS) are associated with pituitary deficiencies. Midline defects elsewhere may alert clinicians to screen for pituitary deficiency (i.e. single central incisor, cleft lip and palate, tracheo-esophageal fistula, omphalocele and gastroschisis, and extrophy of the bladder). In the newborn, pituitary deficiency may present as hypoglycemia (due to GH and/or ACTH deficiency), micropenis (combination of GH and gonadotropin deficiency), or hyperbilirubinemia. Septo-optic-dysplasia, with optic nerve hypoplasia, is often associated with pituitary deficiencies as is holoprosencephaly and absence of the septum pellucidum. Findings on magnetic resonance imaging may include a small or absent anterior pituitary gland, an absent or ectopic posterior pituitary “bright spot,” or a transected pituitary stalk.¹

ACQUIRED CAUSES OF PITUITARY HORMONE DEFICIENCY

Mass-occupying lesions in the hypothalamic area may result in disruption of pituitary function. Tumors such as craniopharyngioma and, less commonly, germinoma and astrocytoma may first present during childhood with growth failure, DI, or visual complaints (or any combination of these). Even in cases when the tumor does not cause loss of pituitary function, surgery may render these children with panhypopituitarism. Hypothalamic hamartomas and pineal tumors are associated with precocious pubertal development during childhood.

Pituitary adenomas are rare in childhood and may or may not actively produce peptide hormones. When active, they most often secrete prolactin (50%) or GH (20%).²

Langerhans cell histiocytosis is a rare disorder that most often presents with DI, but it may also affect the production of other pituitary hormones. Inflammatory, postinfectious, and traumatic lesions of the CNS may cause hypopituitarism as well. CNS irradiation predisposes to the loss of pituitary function, depending on the dose received. Higher doses may precipitate precocious pubertal development.

Clinical signs directly related to pituitary deficiency in children include poor linear growth (GH deficiency), fatigue and malaise (TSH and ACTH deficiency), delayed pubertal development, amenorrhea, or sexual dysfunction (LH and FSH deficiency), hypotension or hypoglycemia (ACTH deficiency). Inability to regulate temperature, appetite, thirst, and vital signs may be seen in hypothalamic dysfunction. Indirect signs of central nervous system lesions, including headaches, vision changes, and other neurological disturbances, may be seen.

ANTERIOR PITUITARY HORMONE DEFICIENCY

DIAGNOSTIC EVALUATION

Diagnosis of anterior pituitary dysfunction typically requires a combination of random hormone measurements and stimulation tests with known secretagogues specific for the pituitary hormone in question.

TSH deficiency can be diagnosed by observing low thyroid hormone (T4) with low or inappropriately normal TSH levels (distinguished from primary hypothyroidism in which TSH is elevated).

Random GH measurements can be diagnostic in the newborn period prior to establishment of the diurnal and pulsatile secretion pattern at 2 to 4 weeks of life. Levels greater than 20 ng/mL are unequivocally sufficient. After this point, or when the diagnosis is not clear, stimulation tests must be performed. Commonly used secretagogues include arginine, clonidine, and glucagon; insulin-induced hypoglycemia was considered a gold standard but is rarely used due to safety concerns. Stimulated growth hormone peaks >10 ng/mL are normal.

Diagnosis of gonadotropin deficiency can be made in the first 6 months for males and before 2 to 3 years of life for females, when the gonadotropin axis is active by measuring random LH and FSH.³ Otherwise diagnosis is generally left until pubertal age.

Secondary or tertiary adrenal insufficiency is diagnosed by observing ACTH and cortisol rise after administration of CRH (1 ug/kg intravenously). Samples for ACTH and cortisol are drawn at baseline and 30, 45, 60, and 120 min after CRH.

• Normal: Basal ACTH increases 2- to 4-fold after CRH; peak cortisol >19 μg/dL

• Secondary adrenal insufficiency: Basal ACTH <10 pg/mL, no response to CRH; peak cortisol <19 μg/dL

• Tertiary adrenal insufficiency: Basal ACTH <10 pg/mL, response to CRH (60-min >10 pg/mL, 120-min >20 pg/mL)

Alternatively a low dose of ACTH (1 μg) with cortisol levels at 0, 30, and 60 minutes can be used to diagnose secondary adrenal insufficiency. Peak cortisol levels of <19 μg/dL are consistent with adrenal insufficiency.⁴

MANAGEMENT

Treatment of anterior pituitary deficiency consists of replacement of the pituitary or target gland hormone. Levothyroxine orally is used for thyroid hormone replacement, subcutaneous growth hormone for GH deficiency, testosterone or estrogen (usually during puberty, though testosterone may be given in neonates to correct micropenis) for gonadotropin deficiency. For secondary adrenal insufficiency, maintenance doses of hydrocortisone may be used, though some have sufficient function to not require daily steroid supplementation. Mineralocorticoid replacement is not needed in secondary adrenal insufficiency, as ACTH does not control the zona glomerulosa. Cortisol replacement should be undertaken prior to thyroid hormone replacement, as this may precipitate adrenal crisis.

• All patients with adrenal insufficiency must be treated during times of stress with high doses of glucocorticoid.

• Oral hydrocortisone 25 to 50 mg/m² every 8 hours given for mild to moderate stress such as fever, emesis, infection, or a minor procedure.

• Intravenous or intramuscular hydrocortisone 100 mg/m² given once for severe stress including shock or major surgery; 100 mg/m² should then be given intravenously over 24 hours divided q4 hours.

• The stress dose should be continued until the patient is recovered from inciting illness, and daily dosage immediately resumed.

DIABETES INSIPIDUS

DI is defined as an inability to concentrate urine despite increasing serum osmolality as a result of inadequate secretion of ADH (central DI) or unresponsiveness of the kidney to ADH (nephrogenic DI). Patients present with excessive drinking (polydipsia) and excessive urine output (polyuria). If thirst is intact and access to free water unrestricted, patients can compensate for urine losses with water intake and remain well hydrated and stable. However, when access to water is interrupted due to illness, fatigue, or lack of an intake thirst center, dehydration and hypernatremia will occur.

DIFFERENTIAL DIAGNOSIS

Potential causes of polyuria and polydipsia include diabetes mellitus (hyperglycemia), hypercalcemia or hypokalemia (can cause ADH unresponsiveness), osmotic diuretics (mannitol, high glucose, intravenous contrast), and psychogenic polydipsia (excess free water intake causing reduced renal responsiveness to ADH and decreased renal concentrating gradient).

DIAGNOSIS AND EVALUATION

To establish the diagnosis of DI, it is necessary to confirm that urinary osmolality remains inappropriately low during a period when serum osmolality has increased to an abnormally high level. This may require fluid restriction and careful monitoring of the clinical status of the patient during a water deprivation test. Fluid restriction in a patient with true DI can result in severe dehydration and hypernatremia and should take place only in a setting in which the patient can be monitored intensively and electrolyte derangement can be corrected immediately. This is not recommended for infants.⁵

If conditions allow for this procedure to be undertaken safely, the following regimen is suggested to demonstrate the presence or absence of DI:

• Test is usually begun in the morning after free access to fluids overnight.

• Patient is NPO with no access to enteral or parenteral fluids.

• Monitor vital signs hourly.

• Monitor weight hourly.

• Monitor urine output hourly.

• Monitor serum and urine osmolality and serum sodium every 2 hours.

The test is stopped for the following:

• Body weight decreases by 3% from baseline.

• Significant orthostatic blood pressure and/or pulse changes are observed.

• Urine osmolality >600 mOsm/kg, suggesting normal ADH secretion and response.

• Urine osmolality reaches a plateau (i.e. less than 10% change over three consecutive measurements).

• Serum osmolality > 300 mOsm/kg H₂O and/or the serum sodium is >145 mmol/L.

With DI, urine osmolality will not rise above 600 mOsm/kg despite high serum osmolality or hypernatremia. Plasma ADH level should be sent at the end of the test to help distinguish central DI (low/absent ADH) from nephrogenic DI (normal levels). Once ADH level is sent, administer desmopressin (1 mg) subcutaneously and continue following urine osmolality and volume for an additional 2 hours. After 2 hours of administering DDAVP, a rise in urine osmolality over (often 50% above baseline) confers a diagnosis of central diabetes insipidus, whereas a rise of less than 10% above baseline confers a diagnosis of nephrogenic diabetes insipidus.⁶

Once the diagnosis of diabetes insipidus is established, two methods can be used as guides for fluid management:

• Method 1: Give maintenance intravenous fluids as normal saline (NS) or ½NS. Replace urine output in excess of 4 mL/kg/hr with D5W or D5/¼NS, depending on the serum sodium level.

• Method 2: Give intravenous fluids for insensible loss of 400 to 600 mL/m²/day as NS or ½NS. Replace all urine output with D5W or D5/¼NS, depending on the serum sodium level.

The second method ensures that the fluids will be adjusted for urine output and protects against overhydration if a change in the patient’s status is anticipated. Serum glucose needs to be monitored closely with both methods because patients may become hyperglycemic, which can worsen the polyuria. For glucose levels higher than 250 mg/dL, an insulin drip may be required (starting dose, 0.03 U/kg/hr).

TREATMENT

Treatment with ADH can be initiated if serum sodium is greater than 145 mEq/L and serum osmolality is greater than 195 mOsm. The dose should be titrated according to the patient’s response to the initial dose. The most flexible regimen is an aqueous pitressin drip. Its extremely short half-life enables rapid changes in dose.

Aqueous pitressin as an intravenous drip:

• Aqueous pitressin is manufactured as 20 U = 1 mL.

• Add 0.1 mL to 20 mL NS, and then add 5 mL of that solution to 500 mL NS so that 1 mL = 1 mU aqueous pitressin.

• The usual starting dose is 0.10 mU/kg/hr. The dose can be adjusted every 30 minutes until the desired trend in serum sodium is noted. Doses higher than 0.8 mU/kg/hr are not likely to increase the antidiuretic effect.

Subcutaneous aqueous pitressin (20 U/mL) can also be used. It has a half-life of 3 to 6 hours.

• The suggested starting dose is 0.05 to 0.1 U/kg per dose subcutaneously (SC)

• Examples:

  • 1 U SC every 4 to 6 hours for infants

  • 2.5 U SC every 4 to 6 hours for toddlers

  • 5 U SC every 4 to 6 hours for children

  • Maximum of 10 U SC every 4 to 6 hours for adults.

Parenteral desmopressin acetate (DDAVP) (0.1 mL = 0.4 μg) has a half-life of 6 to 12 hours (or longer).

• The suggested starting dose is 0.01 to 0.03 μg/kg per dose intravenously (IV) or SC daily or twice daily

• Examples:

  • 0.05 mL SC or IV every 12 hours for infants

  • 0.1 mL SC or IV every 12 hours for toddlers

  • 0.15 mL SC or IV every 12 hours for children

  • Up to 0.5 mL SC or IV every 12 hours for adults

Nasal DDAVP (0.1 mL = 10 μg) has a half-life of 6 to 24 hours.

• Nasal dose of 5 to 20 μg/day (0.05 to 0.2 mL) divided twice daily or daily as needed

• 1 spray = 10 μg or 0.1 mL = 10 μg

• The nasal dose is 10 times the parenteral dose in micrograms

Oral DDAVP (0.1- and 0.2-mg tablets)

• Dose of 0.025 to 0.4 mg orally every 8 to 24 hours

IMPORTANT CONSIDERATIONS

• DI may be transient.

• Posttraumatic or postoperative DI may be followed by the syndrome of inappropriate ADH secretion (SIADH), which may be followed by recurrence of DI (triphasic pattern of DI/SIADH/DI).

• Avoid hyponatremia, which can exacerbate posttraumatic cerebral edema.

• In general, always start with the lowest recommended dose of DDAVP or aqueous pitressin and adjust the dosage as necessary based on ongoing laboratory evaluations.

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an uncommon cause of hyponatremia in the inpatient setting. Hyponatremia (Na <130 to 135 mEq/L) is more often explained by an underlying disease process. However, it is important to consider the diagnosis of SIADH when hyponatremia with decreased urine output develops. The presence of CNS disease or pulmonary disease predisposes to the development of this disorder. By definition, the patient needs to be euvolemic or hypervolemic for the secretion of ADH to be considered “inappropriate.”⁷

DIFFERENTIAL DIAGNOSIS

• Hyponatremic dehydration

• Congestive heart failure

• Inadequate free water excretion secondary to ACTH/cortisol deficiency or thyroid hormone deficiency

• Hyperglycemia, hypertriglyceridemia (factitious)

• Other forms of salt loss (GI)

• Salt wasting via the kidney (should be accompanied by increased urine output)

DIAGNOSTIC EVALUATION

The diagnosis of SIADH should be considered when a patient has decreased urine output and low serum sodium. The evaluation should include strict measurement of input and output, measurement of serum sodium and osmolality, and measurement of urine sodium and osmolality. Typically, in isolated SIADH, the serum sodium and osmolality are low, the urine sodium is above 40 meq/L, and the urine osmolality is above 100 mOsm/kg. Findings should include the absence of edema or dehydration on physical examination, and there should be evidence of intravascular volume expansion (low blood urea nitrogen, low hematocrit, low uric acid) on laboratory evaluation. Causes of factitious hyponatremia (hypertriglyceridemia, hyperglycemia) and other hormonal deficiencies that may interfere with free water excretion (hypothyroidism, glucocorticoid insufficiency) should be ruled out.

TREATMENT

• Restriction of fluid to 400 to 600 mL/m²/day (40% of maintenance) or less (not <25% of daily maintenance)

• Strict input and output; monitor urine specific gravity

• Frequent measurement of serum sodium levels

• If acute life-threatening symptoms are present or if the development of hyponatremia is acute and the sodium level is less than 120 mEq/L with symptoms of neurologic deterioration or brain swelling:

  • Replace urine Na and K losses with 3% saline and appropriate amounts of K.

  • Give 0.5 to 1 mg/kg furosemide by intravenous push, followed by hourly determinations of urine Na and K.

• If necessary, hypertonic (3%) saline can be used to raise serum sodium to 125 mEq/L (3% saline = 0.5 mEq Na/mL; must be given slowly) by using the following formula:

  (125 − Present serum Na) × 0.6 (Na space) × Wt (kg)

• Examples:

  • If you wish to raise serum Na by 10 mEq,

    10 × 0.6 = 6 mEq/kg = 12 mL 3% saline/kg

  • If you wish to raise serum Na by 5 mEq,

    5 × 0.6 = 3 mEq/kg = 6 mL 3% saline/kg

CONSULTATION

• Pediatric endocrinologist

• Pediatric neurosurgeon, as needed

• Pediatric intensivist, as needed

ADMISSION AND DISCHARGE CRITERIA

ADMISSION CRITERIA

• Electrolyte imbalance

• Altered sensorium

• Vasomotor instability

DISCHARGE CRITERIA

• Input and output can be monitored at home, a caregiver can administer medication as needed, and the patient is clinically stable.

• Regular follow-up for monitoring of serum electrolytes and the underlying disease is arranged.

REFERENCES

BACKGROUND

Calcium is the most abundant mineral in the body and is required for proper functioning of numerous intracellular and extracellular processes, including muscle contraction, nerve conduction, hormone release, and blood coagulation. Calcium also plays a unique role in intracellular signaling and is involved in the regulation of enzyme activity. Maintenance of calcium homeostasis is therefore critical. Ionized calcium, which is responsible for the physiologic effects, is maintained under normal conditions within a narrow normal range of approximately 4.5 to 5.3 ng/dL (1.12–1.32 mmol/L), with higher levels in neonates and infants.

The majority of total body calcium exists as bone mineral, with serum calcium representing less than 1% of total body calcium. Although total serum calcium levels are routinely measured, it is the ionized fraction that is biologically active. Total serum calcium levels include both ionized and bound calcium. The total calcium level reflects serum changes in albumin, pH, phosphate, magnesium, and bicarbonate. Ionized calcium may be reduced by exogenous factors such as citrate from transfused blood or free fatty acids from total parenteral nutrition. At physiologic pH, 40% of total serum calcium is bound to albumin, 10% can be bound to bicarbonate, phosphate, or citrate, and the remaining 50% exists in the ionized form.

Calcium absorption and regulation involves a complex interplay between multiple organ systems and regulatory hormones. This tight regulation of circulating calcium is controlled through constant adjustment of parathyroid hormone (PTH) secretion, 1,25-dihydroxyvitamin D (1,25(OH)₂D) production, and renal handling of calcium.

The three major targets for calcium regulation include bone, kidney, and intestine. In bone, PTH stimulates calcium resorption, thereby increasing total and ionized calcium levels. PTH increases intestinal absorption of calcium via activation of 1-α-hydroxylase in the kidney leading to conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25(OH)₂D. Increased levels of 1,25(OH)₂D will increase intestinal absorption of calcium and phosphorus. Without vitamin D-dependent calcium absorption, only 10% of ingested calcium will be absorbed through passive, concentration-dependent absorption. PTH increases renal calcium reabsorption and phosphorus excretion. The majority (60%–70%) of calcium is reabsorbed passively in the proximal tubule driven by a gradient that is generated by sodium and water reabsorption. Individuals with normal kidney function have protection against calcium overload by virtue of their ability to increase renal excretion of calcium and reduce intestinal absorption of calcium by actions of PTH and 1,25(OH)₂D.¹

Calcitonin plays a minor role in decreasing serum calcium levels via its effect on bone and the kidney. Serum calcium levels are detected by calcium-sensing receptors (CaSR) located on the parathyroid glands and renal tubule cells resulting in regulation of PTH secretion and renal reabsorption of calcium, respectively.²

CLINICAL PRESENTATION

HYPOCALCEMIA

Hypocalcemia is frequently observed in the inpatient setting, and incidentally noted biochemical hypocalcemia is often asymptomatic. Symptomatic hypocalcemia occurs in response to a rapid decrease in calcium concentration, as well as in response to the absolute calcium level. Symptoms tend to be more severe if hypocalcemia develops acutely.

The predominant clinical symptoms and signs in children and adolescents include perioral paresthesias, tingling of the fingers and toes, spontaneous or latent tetany, carpopedal spasms, and seizures.³ In neonates, manifestations of hypocalcemia are more nonspecific and include jitteriness, feeding intolerance, lethargy, apnea, and seizures. Physical examination may reveal hyperreflexia, a positive Chvostek sign (twitching of facial muscles after tapping the facial nerve anterior to the ear), or the Trousseau sign (carpopedal spasm after maintaining a blood pressure cuff above systolic blood pressure for 3 to 5 minutes). Less often seen are cataracts, papilledema, rachitic deformities, and abnormal dental development. Chronic mucocutaneous candidiasis and other ectodermal abnormalities in the setting of hypoparathyroidism may suggest autoimmune polyglandular syndrome type 1, whereas other physical findings may suggest pseudohypoparathyroidism type la or DiGeorge syndrome⁴ (Table 71-1).

Hypocalcemia is generally defined as a total serum calcium level of less than 8.5 mg/dL (ionized calcium <4.6 mg/dL or <1.15 mmol/L) in children and adolescents, less than 8 mg/dL (ionized calcium <4.4 mg/dL or 1.1 mmol/L) in term neonates, and less than 7 mg/dL (ionized calcium < 3.2 mg/dL or 0.8 mmol/L) in preterm neonates. If ionized calcium is not available, the corrected calcium can be calculated by adding 0.8 mg/dL to the total calcium for every 1-mg decrease in the serum albumin below 4 mg/dL. Individual laboratory norms should be used when available.⁵

HYPERCALCEMIA

In childhood, hypercalcemia is less common than hypocalcemia and is frequently discovered incidentally on a routine chemistry profile. Because of the potential clinical significance of a slight elevation in serum calcium levels, it is important to obtain an accurate measure by taking the serum albumin concentration and acid–base status into account.

Symptoms of hypercalcemia vary little with age. Lethargy, weakness, inability to concentrate, and depression may develop. Many patients have nausea, vomiting, anorexia, constipation, and weight loss. Patients may become hypertensive with extreme elevations in calcium. Neonates may manifest symptoms of gastroesophageal reflux, lethargy, poor weight gain, and a decrease in linear growth. Elevations in extracellular calcium impair the ability of the distal tubule of the nephron to respond to ADH; therefore hypercalcemic patients may present with polyuria, dehydration, and azotemia.⁶

The normative values for calcium are age dependent. A total serum calcium level of greater than 9.2 mg/dL (ionized Ca >5.8 mg/dL or 1.42 mmol/L) in a premature infant, greater than 10.4 mg/dL (ionized Ca >5.0 mg/dL or 1.22 mmol/L) in a full-term infant, and greater than 10.8 mg/dL (ionized Ca >5.0 mg/dL or 1.22 mmol/L) in a child or adolescent is considered elevated.

DIFFERENTIAL DIAGNOSIS

HYPOCALCEMIA

The etiology of hypocalcemia in pediatrics can vary by the age of the child at presentation. Table 71-1 highlights the clinically important categories of hypocalcemia and associated laboratory findings.

Early Neonatal Hypocalcemia

In infants presenting with hypocalcemia within 48 to 72 hours of birth, the differential diagnosis includes prematurity, birth asphyxia, maternal diabetes, and maternal hyperparathyroidism. In preterm infants, hypocalcemia is essentially due to an insufficient increase in PTH secretion along with a relative resistance to 1,25(OH)₂D. In addition, premature infants have limited intake of milk, which contributes to hypocalcemia.⁷ In infants of diabetic mothers, magnesium deficiency may also play an important role in the development of early neonatal hypocalcemia.⁸ Whenever neonatal hypocalcemia occurs in the absence of these risk factors, the diagnosis of congenital hypoparathyroidism must be considered.

Late Neonatal Hypocalcemia

Late neonatal hypocalcemia presents clinically at 5 to 10 days of life in healthy full-term infants. The three major causes of late neonatal hypocalcemia are phosphate loading, hypoparathyroidism, and magnesium deficiency. Other causes include vitamin D deficiency, PTH resistance, inborn errors of metabolism, and iatrogenic causes (e.g. diuretics, glucocorticoids, and citrated blood products).⁹ Historically, infant formulas with a high phosphorus content have contributed to the development of late neonatal hypocalcemia, but this is seen less commonly with current infant formulas. Phosphate-induced hypocalcemia should be differentiated from congenital hypoparathyroidism. In both situations serum calcium is low and serum phosphorus is high. PTH is appropriately elevated in phosphate-induced neonatal hypocalcemia, however, and the hypocalcemia resolves spontaneously when the neonate is placed on a low-phosphorus formula such as PM 60/40.¹⁰

Childhood Hypocalcemia

Causes of hypocalcemia in children include PTH deficiency, calcium sensing receptor defects, vitamin D deficiency, and resistance to the biologic effects of these calcium-regulating hormones. The differential diagnosis includes vitamin D deficiency, vitamin D resistance, hypoparathyroidism, pseudohypoparathyroidism, metabolic bone disease, and drug effect. Abnormalities in vitamin D metabolism can be seen with renal disease and liver disease. In patients with renal failure, 1α-hydroxylation of 25(OH)D is impaired, and as a consequence, the stored form of vitamin D (25(OH)D) cannot be converted to the biologically active form 1,25(OH)₂D. Hyperphosphatemia may further aggravate hypocalcemia in renal failure and lead to secondary hyperparathyroidism and renal osteodystrophy.

Vitamin D Deficiency

Vitamin D deficiency may be a primary nutritional deficiency or may be secondary to malabsorption. Nutritional deficiency is more common in infants 3 to 36 months of age, with dark skin or from northern latitudes, and in premature or exclusively breastfed infants. Conditions predisposing to malabsorption of vitamin D include celiac disease, cystic fibrosis, pancreatic insufficiency, intestinal bypass, and laxative abuse. Children on anti-seizure medication such as phenobarbital and phenytoin are at increased risk for vitamin D deficiency because of increased hepatic metabolism of vitamin D into inactive metabolites. Biochemical features of rickets are often seen with vitamin D deficiency, including secondary hyperparathyroidism, low serum phosphorus, phosphaturia, high serum alkaline phosphatase, and low 25(OH)D. Clinical features of vitamin D deficiency vary with severity, ranging from a normal exam to severe features seen with rickets including deformities of weight-bearing limbs, growth retardation, frontal bossing of the skull, rachitic rosary, Harrison sulcus, or delayed dentition.¹¹ Radiographic evidence of rickets may also be present on radiographs if fusion of the epiphyses has not yet occurred.

To prevent vitamin D deficiency, the American Academy of Pediatrics (AAP) and the Institute of Medicine have established recommended daily intake guidelines for vitamin D. The current recommended daily intake for infants age 0 to 12 months is 400 international units (IU) daily and for children age 1 to 21 years is 600 IU daily. Any breastfeeding infant, regardless of amount of formula supplementation, should receive a daily supplement of 400 IU per day. If infants are exclusively formula-fed, they do not require vitamin supplementation, as they should receive their daily recommended dose of vitamin D in the formula.¹²

Hypoparathyroidism

Hypoparathyroidism may be secondary to surgery, polyglandular autoimmune disease, infiltrative disease, neck irradiation, or an idiopathic process. The diagnosis of hypoparathyroidism is suggested by low calcium levels, high phosphorus levels, an inappropriately low PTH level, and absence of bone disease on radiographs. Hypomagnesemia may be a causative factor in the development of hypoparathyroidism. Severe hypomagnesemia will suppress PTH secretion, and mild hypomagnesemia will interfere with PTH activity.¹³

Autosomal Dominant Hypocalcemia

is due to a gain of function mutation in the calcium sensing receptor on the parathyroid gland leading to a lowering of the calcium set-point and resulting in hypocalcemia with an inappropriately normal PTH.

Pseudohypoparathyroidism

The diagnosis of pseudohypoparathyroidism (PHP) is characterized by hypocalcemia, hyperphosphatemia, and elevated PTH concentrations. PHP type 1 is a result of a dominantly inherited mutation in GNAS1, the gene that encodes the alpha subunit of the G protein coupled to the PTH receptor, which leads to a failure of signal transduction and end-organ resistance to PTH. The alpha subunit of the G protein is also required for signal transduction for thyroid-stimulating hormone, growth hormone–releasing hormone, luteinizing hormone, and follicular-stimulating hormone. PHP type 1a is the result of an inactivating mutation in GNAS1 on the maternal allele (either maternally inherited or de novo) resulting in characteristic biochemical findings of hypocalcemia, hyperphosphatemia, and elevated PTH, and a phenotype known as Albright’s hereditary osteodystrophy (AHO). The AHO phenotype includes short stature, round face, shortened fourth metacarpal bones, obesity, subcutaneous ossifications, and developmental delay. PHP type 1b has the biochemical findings of PHP but not the AHO phenotype. Patients with PHP type 1c have both the biochemical profile and phenotype similar to 1a, but via a different mechanism. PHP type 2 has hypocalcemia but does not have the AHO phenotype. Pseudopseudohypoparathyroidism is the result of a mutation in GNAS1 on the paternal allele leading to an AHO phenotype, but with normal calcium and phosphorus.¹⁴ Elevated PTH levels, hypocalcemia, and hyperphosphatemia can also be seen in children with renal failure or those who have received treatment with phosphate enemas.

Other Causes

Other conditions associated with hypocalcemia include renal failure, hungry bone syndrome, tumor lysis syndrome, rhabdomyolysis, acute illness, and hypoproteinemia medications (furosemide, calcitonin, bisphosphonates, antineoplastic agents).

HYPERCALCEMIA

Because serum calcium regulation is dependent on PTH, vitamin D, calcium intake, and renal calcium excretion, derangements in any of these systems can produce hypercalcemia. It can be useful to separate the causes into two broad categories: hypercalcemia with inappropriate PTH secretion and hypercalcemia despite appropriate PTH suppression. The causes of hypercalcemia in childhood, along with associated biochemical findings, are summarized in Table 71-2.

Williams Syndrome

Williams syndrome is the result of a large contiguous deletion on chromosome 7q11.23 involving approximately 28 different genes. Patients with Williams syndrome may have hypercalcemia in addition to characteristic features including elfin facies, congenital cardiovascular anomalies, and cognitive impairment. The cause of the hypercalcemia is not currently understood. The hypercalcemia may respond to a diet low in calcium and usually remits between 9 and 18 months of age. It is important to consider Williams syndrome in the setting of hypercalcemia in an infant because of the associated cardiac defects.

Idiopathic Hypercalcemia of Infancy

Idiopathic hypercalcemia of infancy was initially described by Kenny et al. in 1963 in a report of an infant with asymptomatic hypercalcemia.¹⁵ The hypercalcemia improved when vitamin D intake was limited and would recur when given replacement doses of only 400 IU daily, suggesting a problem with the removal or deactivation of vitamin D. The CYP24A1 gene encodes the 24-hydroxylase that breaks down vitamin D metabolites, and recently, loss of function mutations in the CYP24A1 gene has been described in patients with idiopathic hypercalcemia of infancy confirming that the mechanism of hypercalcemia is due to problems with deactivation of vitamin D.¹⁶

Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is a usually asymptomatic condition of parathyroid insensitivity to the normal suppressive effect of calcium on PTH secretion due to a loss of function mutation in the CaSR. This mutation results in an elevation in the normal calcium set-point, leading to hypercalcemia with an inappropriately normal PTH. It is inherited in an autosomal dominant fashion. A homozygous CaSR mutation is characterized by severe and often lethal neonatal hyperparathyroidism.¹⁷

Hyperparathyroidism

Hyperparathyroidism is very rare in childhood. It is characterized by autonomous PTH secretion independent of the serum calcium level. Affected children are hypercalcemic as a result of increased calcium resorption from bone, increased renal reabsorption, and increased intestinal absorption. Serum phosphorus is usually reduced but may be normal. The skeletal erosion is best evidenced in the phalanges and clavicle. Sporadic cases may result from either a parathyroid adenoma or chief cell hyperplasia.

Any child with hyperparathyroidism should be evaluated for multiple endocrine neoplasia (MEN) syndromes. Ninety percent of patients with MEN-I have parathyroid hyperplasia along with a pituitary adenoma or a pancreatic tumor (or both). In MEN-IIA, medullary thyroid carcinoma and pheochromocytoma are the main features, and chief cell hyperplasia is sometimes associated.¹⁸

Hypercalcemia of Malignancy

Hypercalcemia may be caused by an elevation of PTH-related protein (PTH-rp) in patients with malignancies or from increased osteoclastic activity at the tumor site.¹⁹ PTH-rp is secreted by many types of malignant tumors, most notably leukemia, lymphoma, rhabdomyosarcoma, and Ewing sarcoma. Hypercalcemia results from activation of the PTH receptor by PTH-rp.¹²

Hypercalcemia Associated with Granulomatous Disease

Hypercalcemia from excessive extrarenal production of 1,25(OH)₂D may occur in diseases presenting with granulomas. It common in sarcoidosis (present in about half of symptomatic cases) but has also been reported in tuberculosis, fungal diseases (eg. Berylliosis, coccidiomycosis, histoplasmosis, or candidiasis), inflammatory bowel disease, Wegener granulomatosis, and even cat-scratch disease.

Hypervitaminosis D

Vitamin D intoxication is uncommon but can arise from chronic overdosage of vitamin D given for therapeutic purposes or self-administration of vitamin preparations. The resultant hypercalcemia can be severe and prolonged because of storage of vitamin D in fat. Specific therapy includes discontinuation of vitamin D and ingestion of a low-calcium diet.

Hypervitaminosis A

Excessive intake of vitamins may result in vitamin A excess in addition to vitamin D excess. Excess amounts of the fat-soluble vitamin A also increase bone resorption, which may result in hypercalcemia.

Immobilization

Hypercalcemia of immobilization occurs more commonly in children and adolescents than in adults because of a higher rate of bone remodeling at this age. It is seen most frequently after leg fractures, spinal cord injuries, and burns. Hypercalciuria and substantial bone loss are more common than hypercalcemia. PTH and 1,25(OH)₂D are suppressed, and bone biopsy specimens show increased resorption of bone and decreased formation of bone.²⁰

Thiazide Diuretics

Thiazides may cause hypercalcemia as a result of increased renal resorption of calcium and increased calcium binding protein levels.

Other Causes

Other conditions associated with hypercalcemia include adrenal insufficiency, hyperthyroidism, subcutaneous fat necrosis, and high calcium intake.

DIAGNOSTIC EVALUATION

The diagnosis of hypocalcemia or hypercalcemia should be based on the total serum calcium concentration corrected for albumin or on measurements of ionized calcium (if the appropriate tools are available for rapid processing). The evaluation of calcium abnormalities should include total calcium, ionized calcium, phosphorus, magnesium, alkaline phosphatase, parathyroid hormone, 25(OH)D, 1,25(OH)₂D, electrolytes, BUN, creatinine, albumin, and a urine calcium to creatinine ratio. The phosphate level can greatly aid in narrowing the differential as a high phosphate concentration suggests a deficiency of PTH action, whereas a low phosphate concentration favors increased PTH effect. Other laboratory tests to consider if warranted include PTHrp or N-terminary telopeptide, a marker of bone turnover. An electrocardiogram should be performed to monitor for QT prolongation (QTc >0.45s).⁹ The algorithms shown in Figures 71-1 (hypocalcemia) and 71-2 (hypercalcemia) will assist in diagnosis. The diagnostic workup for calcium abnormalities involves a detailed history, examination, and laboratory investigation, as listed in Table 71-3.

MANAGEMENT

HYPOCALCEMIA

Although mild hypocalcemia may not require therapy, any neonate with a serum calcium less than 7.5 mg/dL or any older child with a serum calcium less than 8 to 8.5 mg/dL should be treated to prevent tetany and other symptoms. Oral therapy is preferable whenever possible.

In acute symptomatic hypocalcemia (tetany, seizures), intravenous therapy (IV) is required. For patients with acute life-threatening symptoms of hypocalcemia, IV calcium gluconate is the treatment of choice. Calcium gluconate 10% solution (9.4 mg elemental calcium/mL) can be given by slow intravenous push.²¹ A cardiac monitor must be used because rapid injection can cause serious cardiac dysrhythmias. All calcium salts are locally toxic and can lead to tissue damage if accidental extravasation occurs. A freely running intravenous line should be used to avoid extravasation. When symptoms of hypocalcemia resolve, serial calcium determinations will determine the need for and route of further therapy. Because serum calcium levels may fall gradually after the initial infusion, ongoing treatment may be necessary, and continuous infusions will typically yield better results than multiple boluses.

Mildly symptomatic patients who are unable to take calcium enterally may need calcium gluconate by slow intravenous infusion (every 6–8 hours, depending on subsequent calcium levels). IV calcium infusion is preferred to IV calcium bolus therapy, to reduce the risk of cardiac dysrhythmias.²²

In the absence of tetany or seizures, oral therapy will suffice.

Calcium glubionate is the most suitable agent for infants and young children because it is dispensed as palatable syrup. In older children, tablets of calcium gluconate, carbonate, or lactate can be given. A dosage of 50 mg elemental calcium/kg/day is generally prescribed, with a maximum adult dose of 2000 mg of elemental calcium per day.

If children are vitamin D–deficient, they will require vitamin D supplementation. Two preparations are currently available: vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol). According to the AAP, the recommendations for supplementation are as follows: 1000 IU per day for infants <1 month of age, 1000–5000 IU per day for children age 1 to 12 months, and > 5000 IU per day for children 1 year of age and older. Guidelines for weekly vitamin D supplementation have been provided by the Endocrine Society, at a dose of 50,000 IU once per week for children ages 0 to 18 years. Treatment should continue for 6 weeks, at which time children should be continued on a maintenance dose of vitamin D based on recommended daily intake.^23,24

Calcitriol may be used if the patient is unable to produce 1,25(OH)₂D because of renal disease or severe hypoparathyroidism. However, calcitriol bypasses the body’s ability to regulate vitamin D activity and therefore carries the risk of hypercalcemia and hypercalciuria. It has a short half-life and persists in the body for only 1 to 2 days. Because calcitriol will not replenish vitamin D stores, 25(OH)D should be given as well if a true deficiency of vitamin D is suspected. The usual dosage of calcitriol is 0.25 μg/day but varies with body weight and the disorder for which it is being used. The dosage may be adjusted until calcium levels have improved. Children with significant malabsorption, 1-α hydroxylase deficiency, and vitamin D receptor defects may require high dose calcitriol and/or chronic intravenous calcium therapy.

Individualization of therapy is essential. It is crucial to monitor serum and urinary calcium and creatinine levels frequently to adjust the doses of medications. The goal is to maintain eucalcemia and avoid hypercalcemia and hypercalciuria. Annual renal sonography is also recommended to detect nephrocalcinosis.

HYPERCALCEMIA

Appropriate management of a patient with hypercalcemia depends on the severity and cause of the hypercalcemia. When the calcium concentration is less than 12 mg/dL in an asymptomatic subject, treatment may be delayed until the cause of the hypercalcemia is known. If the total serum calcium concentration exceeds 12 mg/dL or the child is symptomatic, efforts to lower calcium levels should be instituted to prevent the adverse effects of hypercalcemia while awaiting the laboratory results. After initial stabilization, attention should turn to treatment of the underlying cause of the hypercalcemia.

Volume Repletion

The mainstay of initial therapy for acute symptomatic hypercalcemia is vigorous hydration with normal saline. Twice the maintenance infusion rate is recommended initially, if tolerated. Urine output must be closely monitored, and any net fluid deficit should be replaced on an ongoing basis. The goal is to maintain an increased urinary rate and to have input exceed urinary output.

Calcitonin

In cases of severe hypercalcemia, calcitonin (2–4 U/kg) via subcutaneous injection can be given every 6 to 12 hours as needed, but rapid tachyphylaxis to this medication is common and limits its utility.²⁵

Glucocorticoids

Oral glucocorticoids decrease calcium, principally by decreasing absorption from the intestine by inhibiting synthesis of 1,25(OH)₂D from 25(OH)D.²⁶ They also have a role in treating hypercalcemia that arises from granulomatous disease by treating the underlying disease.

Diuretics

Once adequate hydration has been achieved, furosemide (1–2 mg/kg) may be administered intravenously to increase urinary calcium excretion if the serum calcium level is not improving. However, diuretics must be used with caution, as they may lead to fluid losses and worsening dehydration and can increase the risk of nephrocalcinosis with long-term use.

Phosphates

Oral phosphate may be used to bind calcium in the intestine, but its efficacy is limited and its use may result in nausea, abdominal cramps, and diarrhea.

Bisphosphonates

Bisphosphonate therapy should be reserved for refractory cases in which the underlying cause of hypercalcemia is not amenable to other therapies. These agents act via inhibition of osteoclastic bone resorption. Pamidronate (0.5 to 1 mg/kg per dose) may be given intravenously over a period of 4 to 5 hours. The peak effect will not be seen for 48 hours or longer and effects may last up to 24 weeks. Other electrolyte imbalances are frequently seen with bisphosphonate therapy, and patients must therefore be monitored for hypocalcemia, hypophosphatemia, hypomagnesemia, and hypokalemia.²⁷ If renal failure coexists, bisphosphonate therapy may only be indicated in severe cases and at reduced doses. Renal dialysis may be necessary to decrease calcium levels in these patients (severe cases).

Cinacalcet

Cinacalcet is a calcimimetic drug that binds the CaSR to reduce PTH secretion and is used in the treatment of FHH and may be used in cases of hyperparathyroidism (off-label use) to suppress PTH levels in children who are symptomatic and not candidates for surgery.^28,29

Parathyroidectomy

Parathyroidectomy may be indicated for patients with primary hyperparathyroidism. Surgery should be performed by an experienced surgeon to avoid injury to recurrent laryngeal nerve and hypoparathyroidism. If malignancy-derived PTH-rp is the cause of hypercalcemia, treatment of the underlying malignancy is the treatment of choice.

Hemodialysis

Dialysis using a low-calcium dialysate is generally reserved for those patients with life-threatening hypercalcemia that is resistant to medical therapy.

ADMISSION AND DISCHARGE CRITERIA

ADMISSION CRITERIA

Hypocalcemia

• Symptomatic hypocalcemia (unless the diagnosis is hyperventilation)

• Severe hypocalcemia; specifically, a serum calcium level less than 7 to 7.5 mg/dL

• Any newborn with hypocalcemia should be monitored in the neonatal intensive care unit (NICU)

Hypercalcemia

• Symptomatic hypercalcemia

• Severe hypercalcemia, specifically, serum calcium greater than 12 mg/dL (except familial hypocalciuric hypercalcemia)

• Any newborn with hypercalcemia should be monitored in the NICU

DISCHARGE CRITERIA

• Asymptomatic and clinically stable patient

• Arrangements made for regular follow-up to monitor the serum calcium concentration and the underlying disorder

CONSULTATION

• Pediatric endocrinologist

• Pediatric nephrologist

• Geneticist

REFERENCES

BACKGROUND

The adrenal gland is responsible for producing two kinds of signaling molecules: steroid hormones, produced in the outer adrenal cortex, and catecholamines, generated in the adrenal medulla. Steroids can further be divided into mineralocorticoid (aldosterone), glucocorticoid (cortisol) and androgen (dehydroepiandrosterone [DHEA] and dehydroepiandrosterone-sulfate [DHEA-S]) classes. Each of these steroids is stereotypically produced by histologically differentiable cells in a particular layer of the adrenal cortex—the outermost zona glomerulosa produces aldosterone, the middle zona fasciculata produces cortisol, and the innermost zona reticularis produces DHEA and DHEA-S. Control of steroid hormone production and release, however, occurs outside of the adrenal gland; aldosterone is primarily controlled by the renin-angiotensin system and cortisol is regulated by adrenocorticotropic hormone (ACTH) from the pituitary gland, which itself is regulated by hypothalamic secretion of corticotropin-releasing hormone (CRH). Although DHEA-S is the most abundant androgen in serum, the control and function of DHEA and DHEA-S are less well understood.

Similar to the rest of the endocrine system, each of the steroid hormones produced by the adrenal gland can be pathologically elevated or pathologically absent. Specific to steroid producing tissues, two additional types of pathologies occur in the adrenal gland. The first is a defect in enzymatic activity leading to the absence of one steroid and to overproduction of a precursor steroid, with predictable off-target effects (e.g. congenital adrenal hyperplasia). The second defect is an alteration of timing of steroid production/release (e.g. premature adrenarche).

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

Hypothalamic CRH stimulates pituitary ACTH secretion. ACTH regulates adrenal glucocorticoid secretion and is secreted in a pulsatile fashion with amplitude that normally varies as a function of the time of day. This variation is the cause of the diurnal pattern of cortisol secretion. Cortisol secretion is highest early in the morning prior to waking, decreased in the afternoon to evening, and lowest at midnight, or 2 hours after sleep. Negative feedback on the synthesis and secretion of ACTH and CRH is provided by cortisol.¹ In addition to this seemingly simple feedback loop, inflammation, via interleukin-6, stimulates ACTH production leading to cortisol secretion.

ADRENAL CORTEX

Mineralocorticoids maintain electrolyte equilibrium, stabilizing blood volume and blood pressure. They control sodium reabsorption in exchange for potassium in the distal tubule of the kidney. Glucocorticoids are “stress hormones,” and thus they have metabolic activities increasing glucose availability in seemingly counterintuitive ways. They have catabolic effects—increasing protein degradation in muscle, skin, and peripheral adipose tissue, and anabolic effects—enhancing the ability for gluconeogenesis at the liver and increasing central fat storage. In addition, glucocorticoids are permissive for the vasoconstrictive actions of catecholamines.¹ Synthetic analogues of glucocorticoids demonstrate variable anti-inflammatory/gluconeogenic activity, and have variable salt-retaining properties. Androgens promote the growth of pubic and axillary hair.

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

Aldosterone production and secretion is regulated by renin, and to a lesser degree, serum potassium levels.² Renin is produced in the juxtaglomerular apparatus of the kidney and causes the production of angiotensin I. Angiotensin-converting enzyme converts angiotensin I to angiotensin II, which is cleaved to angiotensin III. Angiotensin II and III are potent stimulators of aldosterone synthesis and secretion. A decrease in sodium, blood volume, arterial pressure, and renal blood flow activates the juxtaglomerular apparatus and leads to an increase in renin and thus aldosterone. Increased potassium concentration directly increases aldosterone secretion by the adrenal cortex.

ADRENAL MEDULLA

The medulla produces catecholamines such as dopamine, norepinephrine, and epinephrine. Synthesis of catecholamines also occurs in the brain and sympathetic nerve endings and in chromaffin cells outside of the medulla. The catecholamine metabolites found in urine include vanillylmandelic acid (VMA) and metanephrine.

ADRENAL INSUFFICIENCY

PATHOPHYSIOLOGY

Adrenal steroid hormones are classically thought to mediate their effects via their respective nuclear-receptor family receptors, with aldosterone acting through the mineralocorticoid receptor (MR) and cortisol acting through the glucocorticoid receptor. As noted above, aldosterone has a critical role in salt and water balance, while glucocorticoids have critical roles in metabolism and maintenance of vascular tone. Absence of each or both of these hormones therefore has predictable effects. Isolated absence of aldosterone leads to sodium wasting and hyperkalemia. Similarly, isolated cortisol deficiency (e.g. central adrenal insufficiency) leads to hypotension and risk for hypoglycemia. The context of this simple picture of adrenal insufficiency complicates its pathology in two ways: first, the context can add other non-adrenal problems (e.g. hypothyroidism in panhypopituitarism) and second, if adrenal insufficiency is due to absence of a steroidogenic enzyme, overproduction of cortisol precursors can lead to increases in androgen activity or mineralocorticoid activity. The most common form of congenital adrenal hyperplasia (CAH), 21-hydroxylase deficiency, is characterized by salt-wasting in its severe form. However, in 11-β-hydroxylase deficiency, initial salt wasting is usually mild. Lack of negative feedback through the glucocorticoid receptor at the levels of the hypothalamus and pituitary by cortisol paradoxically leads to excess mineralocorticoid activity and consequent elevation in sodium and hypertension. Thus different forms of CAH exert their effects variably due to altered androgen (usually increased) and mineralocorticoid (sometimes increased, and in other cases decreased) activity. There are not as of yet clinically described deficiencies in DHEA, DHEA-S, or adrenal catecholamines.

CLINICAL PRESENTATION

The clinical manifestations and age at onset of adrenal insufficiency depend on its cause. Presentation at birth or soon after is seen with adrenal hypoplasia, defects in steroidogenesis, and pseudohypoaldosteronism. In these diseases, patients present with symptoms of salt wasting and failure to thrive, vomiting, lethargy, anorexia, and dehydration. In older children, adrenal insufficiency caused by Addison disease presents with muscle weakness, lassitude, anorexia, weight loss, wasting, hypotension, and abdominal pain.

An adrenal crisis may present with hypoglycemia, hypotension, cyanosis, cold skin, and/or a weak, rapid pulse. In disorders associated with excess ACTH (e.g. congenital adrenal hypoplasia, CAH, Addison disease, adrenoleukodystrophy, and ACTH resistance), there can be hyperpigmentation of the skin and oral mucosa as a result of increased melanocyte-stimulating hormone (MSH) levels.

Because cortisol signaling is permissive for catecholamine action, the hypotension is particularly challenging to manage as it is classically nonresponsive to catecholamines or fluid resuscitation, and can be fatal.

The clinical features of CAH are determined by the specific enzyme deficiency and include virilized female for deficiencies in 21-hydroxylase and 3β-hydroxysteroid dehydrogenase (3β-HSD) and undervirilized males as seen in cholesterol desmolase and 3β-HSD deficiencies. Deficiencies of either 11-hydroxylase or 17-hydroxylase deficiencies may present with ambiguous genitalia but not with symptoms of adrenal insufficiency.

DIFFERENTIAL DIAGNOSIS

Because adrenal insufficiency presents primarily with lethargy, hypotension, dehydration, or hypoglycemia, the differential diagnosis is broad for these patients. Other diseases that may present acutely with these symptoms include sepsis, severe or longstanding diarrhea, or hyperinsulinism. Classically, we think of hyperinsulinism and diarrhea resulting in severe dehydration presenting in infancy. In the absence of crisis, adrenal insufficiency may present as decreased exercise tolerance or lethargy, particularly in the afternoon, and/or muscle aches or nonspecific complaints. The differential for this presentation is broad, but also includes, notably, hypothyroidism as well as depression.

Once the diagnosis of adrenal insufficiency is made, the specific cause needs to be established. Adrenal insufficiency can be due to abnormalities of the hypothalamus, pituitary, and adrenal cortex (Table 72-1). Hypothalamic and pituitary deficiencies are discussed in a separate chapter. Familial glucocorticoid deficiency, or ACTH resistance, is an autosomal recessive disorder in which there is an isolated deficiency of glucocorticoid. In this disease aldosterone production is normal and there is no salt wasting. In Allgrove syndrome (triple A syndrome), ACTH resistance may occur in association with achalasia and alacrima.

The most common cause of adrenocortical insufficiency is salt-losing CAH, or 21-hydroxylase deficiency, it accounts for 90% to 95% of CAH and occurs in roughly 1 in 13,000 live births. Lipoid adrenal hyperplasia and 3β-HSD deficiency are less common forms of CAH, in which both cortisol and aldosterone are deficient.

Isolated deficiency of aldosterone is a rare autosomal recessive disorder. Pseudohypoaldosteronism occurs when there is target organ unresponsiveness to aldosterone. It can be limited to the kidney or may involve multiple target organs (sweat glands, salivary glands, and colon). Both autosomal dominant and autosomal recessive inheritance has been reported.

Addison disease is acquired primary adrenal insufficiency due to destruction of the adrenal cortex with maintenance of the adrenal medulla. The most common cause of acquired adrenal insufficiency worldwide is tuberculosis infection–mediated destruction of the adrenal cortex. However, in the industrialized world, the most common cause of acquired adrenal insufficiency is autoimmune destruction of the adrenal cortex. Waterhouse–Friderichsen syndrome is adrenal insufficiency hemorrhagic destruction of the adrenal glands in the context of systemic infection, most commonly by Neisseria meningitidis.

Addison disease occurs with other endocrinopathies, such as autoimmune polyglandular syndrome (APS) type 1. APS type 1 is an autoimmune polyendocrinopathy which also presents with candidiasis and ectodermal dystrophy. Patients typically have mucocutaneous candidiasis, hypoparathyroidism, and Addison disease. Gonadal failure, alopecia, vitiligo, enamel hypoplasia, intestinal malabsorption, chronic acute hepatitis, and hypothyroidism can also occur in APS type 1. Addison disease can also occur in APS type 2, which is characterized by Addison disease, autoimmune thyroid disease, and type 1 diabetes mellitus, but gonadal failure, vitiligo, alopecia, and atrophic gastritis can commonly occur. APS type 2 is associated with HLA-DR3 and HLA-DR4 markers, and multiple generations can be affected.

Adrenoleukodystrophy is caused by the accumulation of very long chain fatty acids in peroxisomes resulting in adrenal cortical failure and central nervous system demyelination, and is associated with progressive cognitive deterioration. It is most often an X-linked recessive trait, and more than 100 mutations in the gene have been described.

Premature adrenarche is early activation of the hypothalamic-pituitary-adrenal (HPA) axis. It is associated with earlier initiation of puberty, and on lab exam may manifest only as pubertal concentrations of DHEA or DHEA-S prior to pubarche. Such activation is not to be confused with late-onset CAH. This activation often results in referral of school-age children to endocrinologists because of early appearance of pubic or axillary hair. These children do have an advancement of their bone age but its effect on final height is not certain, and there is not currently any treatment to alter the course of this disease.

DIAGNOSTIC EVALUATION

In those presenting with any of the cardinal symptoms of classic adrenal crisis (i.e. hypoglycemia and/or impending cardiovascular collapse), a serum ACTH and cortisol level should be drawn if possible prior to emergent treatment with stress-dose steroids. Because steroid administration is urgent in these cases, steroids should not be delayed pending the results of these tests. Elevation of both ACTH and cortisol levels can provide post-treatment reassurance of normal adrenal function.

The following lab findings are associated with adrenal insufficiency:

• Hyponatremia

• Hyperkalemia

• Acidosis

• Hypoglycemia

• Increased plasma renin

• Increased urine sodium and chloride

• Decreased urine potassium

• Eosinophilia in the complete blood count

Abdominal radiographs may show calcification of the adrenal gland secondary to infection or hemorrhage. Abdominal ultrasound may reveal enlarged adrenals bilaterally in CAH. Initial screening for glucocorticoid deficiency (in the non-critically ill child) is usually performed with an AM cortisol.⁴ If this value is below 10 ug/dL a stimulation test is performed. Some clinicians believe in the possibility of normal basal secretion but absent stress reserve and so will perform the stimulation test irrespective of the result of the AM cortisol. Many institutions initially perform an ACTH stimulation test, and some perform a CRH stimulation test.⁴ Isolated defects in aldosterone are associated with increased aldosterone precursors. ACTH levels are increased in primary adrenal insufficiency and decreased in secondary and tertiary insufficiency. Renin levels are increased and aldosterone levels are decreased in salt-wasting CAH, isolated defects in aldosterone synthesis, adrenal hypoplasia, and Addison disease. Both renin and aldosterone levels are increased in pseudohypoaldosteronism. Elevation of adrenal steroid precursors and androgens is found in CAH.

MANAGEMENT

Treatment of adrenal insufficiency includes both acute and chronic therapy. Adrenal crisis requires immediate and vigorous treatment with stress-dose steroids (100 mg/m² of hydrocortisone or glucocorticoid equivalent), dextrose, and normal saline to correct hypoglycemia and salt loss. For those with both glucocorticoid and mineralocorticoid deficiency, chronic treatment includes oral hydrocortisone two to three times daily (6–12 mg/m²/day of hydrocortisone or glucocorticoid equivalent) and the mineralocorticoid fludrocortisone once daily. In some cases sodium chloride supplementation is required. Plasma renin and serum sodium concentrations may be used to monitor the adequacy of mineralocorticoid replacement. Morning ACTH may be monitored to ensure lack of overtreatment with glucocorticoid. Increased doses of hydrocortisone need to be given during periods of stress (e.g. fever, illness, surgery). Mineralocorticoid replacement is not necessary in patients with isolated corticotropin deficiency or ACTH resistance (isolated glucocorticoid deficiency). Glucocorticoid therapy for CAH not only replaces the deficient cortisol but also suppresses the excessive ACTH secretion, which results in a decrease in adrenal androgen secretion.

When patients with chronic adrenal insufficiency are admitted to the hospital with acute illness, they may have a relative insufficiency of steroids, and present with symptoms of adrenal insufficiency even though they are provided their maintenance therapy. It is critical these children receive stress-dose steroids during acute illness.

ADMISSION AND DISCHARGE CRITERIA

Criteria for admission include:

• Electrolyte imbalance

• Vasomotor instability

• Psychosis

Criteria for discharge include:

• Asymptomatic and clinically stable patient

• Regular follow-up arranged for monitoring serum electrolytes and/or blood pressure and the underlying disease

• Patient and/or patient’s guardians/caretakers are instructed on stress dosing, including IM injection in the context of inability to take oral stress doses.

CONSULTATION

• Pediatric endocrinologist

• Geneticist for patients with genetic forms of adrenal insufficiency

• Pediatric neurologist for patients with adrenoleukodystrophy

HYPERADRENAL STATES

PATHOPHYSIOLOGY

Similar to adrenal insufficiency, the pathophysiology of hyperadrenal states follows in a fairly straightforward fashion from the physiological effects of each of the adrenal hormones. Aldosterone excess leads to increases in salt retention and potassium wasting. Cortisol excess leads to metabolic effects resulting from peripheral catabolism and central anabolism as well as vascular effects. Finally, catecholamine excess causes increased vascular tone and antagonism of insulin action via β-adrenergic mechanisms.

CLINICAL PRESENTATION

Features of glucocorticoid excess include central adiposity, hypertension, moon facies, plethora, capillary fragility, violaceous striae (particularly on the abdomen), dorsal and supraclavicular fat pads, acne, depression, and possible associated signs of abnormal virilization. In addition, impaired growth velocity and short stature may be present, as well as pubertal delay and amenorrhea. Osteoporosis and renal stones are also consequences of chronic glucocorticoid excess. Patients with hyperaldosteronism have moderate or severe hypertension, hypokalemia, weakness, tetany, growth failure, and intermittent paralysis.

Excess production of catecholamines occurs in pheochromocytoma and neuroblastoma, and may present differently in children than in adults. In children with pheochromocytoma, the symptomatology of catecholamine excess is somewhat different from that seen in adults. In children, more than 90% of hypertension is sustained and is not paroxysmal (as observed in adults with this pathology). While the hypertension is sustained, many of the most common complaints (headache, sweating, nausea, abdominal pain, and palpitations) may occur in paroxysmal fashion. Sweating, visual changes, nausea and vomiting, weight loss, polyuria, and polydipsia are more common in children than in adults. Pallor (and infrequently flushing), weight loss, weakness, and fatigue may also be noted. Symptoms may be precipitated by exercise, Valsalva maneuvers, alcohol ingestion, and intubation. Drugs such as beta-blockers, nicotine, and tricyclic antidepressants can also precipitate symptoms. If the catecholamine excess has been longstanding, cardiac examination may reveal left ventricular hypertrophy or even cardiomyopathy, and there may be changes on fundoscopic examination. Elevated fasting plasma glucose levels and glycosuria may be present.

Patients with neuroblastoma may present with an abdominal mass, weight loss, bone pain, anemia, flushing, headache, and hypertension.

The cardinal symptoms of adrenal excess are related to increased vascular and metabolic activity. Other diseases that may present acutely with some of these features include obesity, hyperthyroidism or hypothyroidism, and acutely, particularly appearing similar to catecholamine excess, ingestion of muscarinic antagonists. Obesity often occurs with hypertension and insulin resistance and can also be characterized by striae, as well as a buffalo hump distribution of fat. However, obesity is usually associated with increased growth as opposed to the growth plateau usually associated with glucocorticoid excess. Additionally, the degree of hypertension in glucocorticoid excess is generally in excess of that observed with obesity. Hypothyroidism can lead to obesity, hypertension, and growth failure, but is not usually associated with striae or moon faces. Conversely, while hyperthyroidism can lead to hypertension, it is usually associated with thinness rather than central obesity.

DIFFERENTIAL DIAGNOSIS

The most common cause of glucocorticoid excess (Cushing syndrome) is long-term administration of systemic corticosteroids or ACTH. Outside of iatrogenic causes, the most common cause in older children is bilateral adrenal hyperplasia. Girls and boys are affected equally. It may be due to hypersecretion of ACTH from the pituitary gland (Cushing disease), or ectopic ACTH secretion. Excess cortisol production may also be caused by adrenocortical nodular dysplasia and adrenal tumors, including carcinoma and adenoma. Tumors are the most common cause of glucocorticoid excess in infants, with an observed female preponderance of 3:1.

Primary hyperaldosteronism can be caused by an aldosterone-secreting adenoma, which mainly affects girls, or by bilateral micronodular adrenocortical hyperplasia, which affects adolescents. A rare form of low-renin hypertension is glucocorticoid-remediable hyperaldosteronism. Primary hyperaldosteronism is independent of the renin-angiotensin-aldosterone system (RAAS) and is rare in children. Apparent mineralocorticoid excess syndrome is a form of low-renin hypertension with exceedingly low levels of mineralocorticoids. The causes of secondary hyperaldosteronism include an activated RAAS, which may be seen in renovascular hypertension. Renin production can also be enhanced in response to sodium loss or volume depletion and in edematous states such as congestive heart failure, cirrhosis, and nephrotic syndrome.

The three catecholamines produced in humans are dopamine, norepinephrine, and epinephrine. They are synthesized in the sympathetic neurons, chromaffin tissue (including, but not limited to, the adrenal medulla), and brain. The source of excessive catecholamine production is most often the adrenal medulla. Tumors of the adrenal medulla include pheochromocytoma, neuroblastoma, and ganglioneuroma. All three have been reported to produce catecholamines in excess, and to occur as “silent tumors” without any of the enzyme activity required to elaborate catecholamines from tyrosine.² Pheochromocytoma is a rare tumor seen uncommonly in childhood. The tumors most often involve the adrenal medulla but may occur at the site of extra-adrenal chromaffin tissue. Extra-adrenal pheochromocytomas are also called paragangliomas. Children with pheochromocytoma are more likely than adults to have bilateral tumors, multiple tumors, and tumors at extra-adrenal sites. Extra-adrenal tumors are usually within the abdominal cavity.⁵ Neuroblastoma is the second most common malignant solid tumor in childhood. Some 35% arise from adrenal neuroectoderm and can spontaneously regress in infants younger than 6 months.

Elemental mercury interferes with catecholamine catabolism, resulting in elevated levels of catecholamines and tachycardia, hypertension, and sweating. Mercury toxicity should be considered in patients suspected of having a neuroendocrine-secreting tumor.

EVALUATION

Initial screen for glucocorticoid excess is a midnight salivary cortisol. If this is positive, the next appropriate screen is a 24-hour urinary free cortisol. Laboratory evaluation of glucocorticoid excess reveals elevated midnight serum cortisol and 24-hour urinary free cortisol levels. Polycythemia, lymphopenia, and decreased eosinophils can be present. Patients may have abnormal glucose tolerance or diabetes, as well as hypokalemia. If the 24-hour urinary cortisol is positive or equivocal in the context of a high index of suspicion, a two-step or overnight dexamethasone suppression test can aid diagnosis. In normal children, administration of dexamethasone at 12 AM will usually suppress the next 8 AM cortisol level to less than 5 mg/dL. In patients with pathologic excess of cortisol, levels will not be suppressed in response to an overnight dexamethasone suppression test. In the absence of suppression after a test, a two-step (low-dose and high-dose) suppression test should be performed. In the low-dose test, 30 μg/kg/day is administered in four divided doses for 2 days. The high-dose test consists of administration of 120 μg/kg/day in four divided doses for 2 days. In patients with Cushing disease, cortisol levels will not be suppressed with low-dose but will be with high-dose dexamethasone.⁴ A computed tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen can rule out an adrenal tumor, and MRI of the head can help rule out an ACTH-secreting pituitary tumor.

To diagnose primary hyperaldosteronism, ideally serum renin, aldosterone, sodium, and potassium should be obtained simultaneously. Patients with primary hyperaldosteronism have hypokalemia, suppressed plasma renin activity, and increased plasma and urinary aldosterone levels. Dexamethasone (0.25 mg every 6 hours) will suppress aldosterone and normalize blood pressure in glucocorticoid-responsive hyperaldosteronism only. If a tumor is suspected, abdominal CT or MRI and adrenal vein catheterization can help localize the tumor. Patients with secondary hyperaldosteronism are often normotensive and may have hypokalemic alkalosis and hyperreninemia.

In psychiatric disease such as depression, the diurnal variation of cortisol production flattens out due to increased nighttime production of cortisol. This alteration can lead to false positives on screening midnight salivary cortisol but usually the overall cortisol production as measured by 24-hour urinary cortisol is normal. The increase in nighttime cortisol is generally thought not to be a primary defect; however, work in experimental animals, as well as our understanding of the relationships between stress and depression, suggest that in and of itself this loss of diurnal variation can cause depression.

In those with catecholamine excess, the catecholamines or their metabolites may be elevated in serum or urine in a ratio that is dependent on the enzyme activity of each individual tumor. Dopamine is metabolized to homovanillic acid (HVA), norepinephrine to normetanephrine, and epinephrine to metanephrine. Metanephrine and normetanephrine are then further metabolized to VMA. The diagnosis of pheochromocytoma can be very difficult to make because the tumors may secrete catecholamines episodically. Catecholamine levels may also be spuriously elevated by medications or elevated in response to other stressful stimuli. A plasma metanephrine or 24-hour urine metanephrine are currently recommended as the initial screening test. Total metanephrines may be the most sensitive single test, but evaluation of a 24-hour urine collection for fractionated catecholamines (norepinephrine, epinephrine, and dopamine) and VMA increases diagnostic sensitivity.

If only mild to moderate elevations (greater than the upper limit of normal but less than four times the upper limit of normal) are found in urine metanephrines, the biochemical abnormality should be confirmed by a second 24-hour urine collection before any radiologic or nuclear imaging is undertaken. If a high index of suspicion is present, normal results from a single 24-hour urine collection are not sufficient to rule out the diagnosis. The patient may need to have repeated measurements of urine metanephrines to document an abnormality. Provocative tests should be avoided because they may be dangerous, and suppression tests are not usually helpful.

If significant elevations of catecholamines or metanephrines (or both) are found, radiographic localization with a CT scan or MRI of the abdomen or total body ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) scintigraphy should be undertaken. Extra-adrenal pheochromocytomas may take up ¹³¹I-MIBG less avidly than adrenal pheochromocytomas.

Children with pheochromocytoma should be screened for the genetic disorders in which they commonly occur, including multiple endocrine neoplasia IIA and IIB, von Hippel-Lindau disease, and neurofibromatosis.⁵ As in adults, the majority are benign lesions, but approximately 10% behave in a malignant fashion. Malignancy can be defined only by metastasis to an area of the body that lacks chromaffin tissue because there is no gross or microscopic pathologic finding that reliably predicts malignant behavior.

VMA and HVA spot urine tests are useful screening tests for neuroblastoma. Imaging testing should be instituted to find the primary tumor. The majority are in the abdomen, and an ultrasound or abdomen/pelvic CT should be considered. If there is further clinical suspicion, imaging of chest or thoracic spine is indicated for extraabdominal primary tumors.

MANAGEMENT

Treatment of glucocorticoid excess is based on its cause. A benign cortical adenoma is treated by surgical removal of the tumor. Adrenocortical carcinoma will frequently have metastasized at the time of diagnosis. Surgical resection, plus chemotherapy when indicated, is the current treatment. Cushing disease is often treated with transsphenoidal pituitary microsurgery. These patients require perioperative and postoperative steroid treatment until their HPA axis recovers, and some patients will develop postoperative hypopituitarism.

Treatment of mineralocorticoid excess involves correction of hypokalemia and underlying renin and aldosterone abnormalities. Definitive therapy may include aldosterone antagonists, glucocorticoids, or surgery, depending on the cause.

Pheochromocytomas must be surgically removed. Classically, alpha-blockade of 1 to 3 weeks’ duration has been recommended before surgery, although shorter courses have been reported in the literature. Phenoxybenzamine is considered the drug of choice for alpha-blockade. Beta-blockade should never be implemented unless adequate alpha-blockade has been established first. Beta-blockade in the absence of alpha-blockade can exacerbate hypertension by blocking the action of vasodilating β₂-receptors without blocking the action of the vasoconstricting α₁-receptors. In general, beta-blockade is used as an adjunctive therapy only in cases in which alpha-blockade has induced severe tachycardia or tachyarrhythmias. All patients with the diagnosis of pheochromocytoma require lifelong follow-up.

Children with neuroblastoma may require surgical excision of the primary lesion, chemotherapy, and bone marrow transplantation.

ADMISSION AND DISCHARGE CRITERIA

Criteria for admission include:

• Electrolyte imbalance

• Vasomotor instability

• Psychosis

Criteria for discharge include:

• Adequate control of symptoms and clinically stable patient

• Regular follow-up arranged for monitoring serum electrolytes or blood pressure (or both) and the underlying disease

CONSULTATION

• Pediatric endocrinologist

• Pediatric surgeon, as needed

• Pediatric oncologist, as needed

REFERENCES