Endocrine Disorders
Adrenal Insufficiency
Mary P. White
Background
Adrenal glands, located on the kidneys, produce three types of hormones:
Glucocorticoid hormones (e.g., cortisol, corticosterone).
Maintain glucose control by affecting protein and carbohydrate metabolism.
Inhibit glucose uptake in muscle and adipose tissue.
Stimulate gluconeogenesis, particularly in the liver.
Respond to stress by upregulating the expression of anti-inflammatory mediators and downregulating the expression of proinflammatory mediators.
If prolonged exposure to glucocorticoids, Cushing syndrome develops.
Obesity, muscle wasting/weakness, decreased glucose tolerance/hyperglycemia, buffalo hump.
Mineralocorticoid hormones (e.g., aldosterone, dehydroepiandrosterone).
Maintain the balance of sodium and potassium in the body.
When aldosterone is increased, aldosteronism develops.
Hypernatremia and hyperkalemia, resulting in hypertension.
If androgens are increased, sex characteristics will be affected.
Sex hormones (e.g., androgens, progestins, and estrogens).
Disorders affecting the adrenal cortex lead to inadequate or absent production of hormone(s).
Disorders are either congenital or acquired.
Adrenal insufficiencies can be acute (adrenal crisis) or chronic (Addison disease).
The most common causes of acute adrenal insufficiency are Waterhouse-Friderichsen syndrome, sudden withdrawal of long-term corticosteroid therapy, and stress states in patients with chronic adrenal insufficiency.
Primary Adrenal Insufficiency
Definition
Impairment in the adrenal glands.
Glucocorticoid and mineralocorticoid hormones, particularly cortisol, are not produced in sufficient amounts.
Etiology/Types
Congenital primary adrenal insufficiency.
Congenital adrenal hyperplasia (CAH) is the most commonly identified cause of primary adrenal insufficiency in children.
Autosomal recessive disorder: defect in an enzyme (largely, 21-hydroxylase deficiency) required in the synthesis of cortisol to cholesterol.
Results in dysfunction in the synthesis of adrenal steroids.
Incidence: 1 in 10,000 to 18,000 live births.
Females have higher incidence; most commonly diagnosed at birth.
Males usually present with a life-threatening salt-wasting crisis in the first month of life.
Newborn screen has incorporated CAH testing in most states in the United States, decreasing the time to diagnosis, particularly for males.
Acquired primary adrenal insufficiency.
Includes autoimmune etiologies (autoimmune destruction of adrenal cortex) and iatrogenic causes such as hemorrhage, trauma, drug effects, pituitary tumor, or infection.
Clinical Presentation
CAH.
Ambiguous genitalia at birth.
If not diagnosed at birth, symptoms will present within 1 to 4 weeks of life.
Vomiting, dehydration, cardiac arrhythmias, hyponatremia, hyperkalemia, or salt-losing crisis, resulting in circulatory collapse.
Adrenal insufficiency.
Symptoms can be slower to progress.
Fatigue, loss of weight, hyperpigmentation of the creases of the skin, nausea, vomiting.
Prolonged recovery from an illness may prompt further investigation of multiple vague symptoms, leading to the diagnosis.
Adrenal crisis.
Acute symptoms: life-threatening disorder.
Vomiting, abdominal pain, hypovolemic shock.
May occur in individuals with chronic adrenal insufficiency experiencing a stressor such as an intercurrent illness, surgical procedure, or in cases of abrupt cessation of glucocorticoid administration.
Diagnostic Evaluation
17-OHP levels; often completed on newborn screening.
Morning 17-OHP levels may be elevated in a partial enzyme deficiency.
Testosterone level; females (elevated).
Androstenedione; males and females.
Karyotyping important for ambiguous genitalia.
Adrenocorticotropic hormone (ACTH) stimulation test may be necessary to confirm diagnosis.
Significant rise in cortisol level 30 to 60 minutes following ACTH injection.
Decreased cortisol response also seen in some cases.
Secondary Adrenal Insufficiency
Definition
Caused by an impairment in the hypothalamus or pituitary gland.
Lack of corticotrophin-releasing hormone from the hypothalamus and/or ACTH secretion from the pituitary, resulting in poor function of the adrenal cortex.
Mineralocorticoid function is preserved in secondary adrenal insufficiency.
Congenital secondary adrenal insufficiency.
Congenital causes of secondary adrenal insufficiency include septo-optic dysplasia, corticotropin-releasing hormone deficiency, and maternal hypercortisolemia.
Acquired secondary adrenal insufficiency.
Most common cause is abrupt discontinuation of glucocorticoid therapy.
Glucocorticoids, administered in any route, can result in suppression of the hypothalamic-pituitary-adrenal axis.
This occurs with glucocorticoid therapy of as short as 2 weeks’ duration.
Inflammatory disorders, tumors, radiation therapy, or trauma are other causes.
Diagnosis
Metabolic acidosis, hyponatremia, hypoglycemia, hyperkalemia, low or normal plasma cortisol, elevated ACTH.
ACTH stimulation test.
Measures how well the adrenal glands respond to the administration of ACTH.
See Common Diagnostic Testing at the end of this chapter for more information.
Management: Primary and Secondary Adrenal Insufficiency
Glucocorticoid administration.
Goal is to replace physiologic glucocorticoid production.
CAH: 10 to 20 mg/m2/day of oral hydrocortisone daily.
Adrenal insufficiency: 6 to 9 mg/m2/day oral hydrocortisone daily.
The dose of glucocorticoid should be adjusted in patients with fever or illness to reflect the normal physiologic response to stress (stressed states result in elevated cortisol levels in a normal host).
Stress dosing: hydrocortisone 25 to 50 mg/m2/day IV/IM.
For severe illness or surgical procedures, higher doses may be indicated: hydrocortisone 50 to 123 mg/m2/day IV.
Mineral corticoid maintenance.
CAH and salt-losing forms of adrenal insufficiency: 0.1 to 0.2 mg oral fludrocortisone acetate daily.
Infants require 17 to 34 mEq of sodium supplementation daily.
Monitor blood pressure and electrolytes.
PEARL
Adrenal insufficiency can be life-threatening and should always be considered in an individual recently receiving steroids.
Cerebral Salt Wasting
Michele Goodwin
Sharon Y. Irving
Background
Occurs following an acute central nervous system (CNS) injury.
Occurs in the setting of both hypovolemia and hyponatremia.
Reports of cerebral salt wasting (CSW) in the pediatric population first appeared in the 1980s.
Syndrome of inappropriate antidiuretic hormone (SIADH) is more common than CSW in patients with hyponatremia and CNS disease.
It is important to distinguish between SIADH and CSW as treatments for the disorders are different.
Definition
Characterized by increased renal loss of salt during or following intracranial insult.
Results in volume depletion and hyponatremia.
Can be described as a volume-depleted clinical state accompanied by renal salt wasting.
Typically, the onset occurs within the first few days of an inciting intracranial injury, surgery, or disease process.
Etiology
Unclear etiology.
Strong association with elevation in the circulating brain and atrial natriuretic peptides, along with an alteration in the neuronal control of the kidneys.
May lead to the inhibition of the renin-angiotensin-aldosterone system, causing abnormal renal reabsorption of sodium and triggering the release of antidiuretic hormone (ADH) necessary to maintain intravascular volume.
May be associated with the following clinical conditions:
Traumatic brain injury.
Intracranial surgery.
Meningitis.
Encephalitis.
Subarachnoid hemorrhage.
Pathophysiology
Poorly understood.
Hypothesized mechanisms are thought to be related to impaired sodium reabsorption likely due to the release of brain natriuretic peptide, increased atrial natriuretic peptide, and/or decreased central sympathetic activity.
The natriuretic peptides are believed to cause the inhibition of renal salt reabsorption by the kidneys and the restriction of renin and aldosterone release; both affect sodium levels and fluid volume (Figure 7.1).
 FIGURE 7.1 • Cerebral Salt-Wasting Pathophysiology. (From Yee, A. H., Burns, J. D., & Wijdicks, E. F. (2010). Cerebral salt wasting: Pathophysiology, diagnosis, and treatment. Neurosurgical Clinics of North America, 21, 339-352 with permission.) |
Clinical Presentation
Headache.
Nausea/vomiting.
Depressed/altered mental status.
Lethargy.
Dehydration.
Agitation.
Seizures.
Hypotension.
Coma.
The rate of renal sodium loss, the degree of hyponatremia, and the overall fluid status impact the severity of the presenting symptoms.
Diagnostic Evaluation
Laboratory studies:
Serum sodium <135 mEq/L.
Serum osmolarity <280 mOsm/kg.
Urine sodium >80 mEq/L.
Urine osmolarity >200 mOsm/kg.
Urine specific gravity >1.010.
Urine output 2 to 3 mL/kg/hour.
Head CT/MRI.
Can identify structural abnormalities/pathophysiologic changes (e.g., arteriovenous malformation, tumor or other space-occupying lesion, hemorrhage).
Lumbar puncture.
CNS infection (in cases of CNS-infection-triggered CSW).
Management
Distinguish between CSW and SIADH.
Treatment is different for these conditions.
Identify and treat the underlying cause.
Frequent monitoring of serum sodium levels and fluid balance.
Sodium replacement using a non-dextrose-containing isotonic or hypertonic fluid at an approximate rate of 0.5 to 1 mEq/hour.
Limit serum sodium level rise to no more than 10 to 12 mEq/day.
The demyelination that occurs with rapid osmotic fluid shifts can result in irreversible neurologic damage.
If the patient presented with acute neurologic changes, this may be related to the rate of serum sodium loss.
In this instance, it may be more appropriate to provide non-glucose-containing hypertonic fluid until symptoms abate.
Consultation with appropriate subspecialty services, including neurosurgery and neurology.
Patient/family education regarding CSW etiology, diagnostic testing, and treatment.
PEARLS
CSW should always be considered in early-onset hyponatremia accompanied by hypovolemia that follows an intracranial insult.
Avoiding too rapid a rise in serum sodium levels can reduce the risk of central pontine demyelination of white matter in brain.
Diabetes Insipidus
Allison Thompson
Background
A disorder caused by insufficient secretion of ADH by the pituitary gland (neurogenic), or failure of the kidneys to respond to circulating ADH (nephrogenic).
Characterized by increased thirst and the excretion of large amounts of dilute urine.
Etiology
Neurogenic (central diabetes insipidus [DI]).
Genetic: typically X-linked recessive.
Examples: Wolfram syndrome.
A rare inherited autosomal recessive condition.
Affects 1 in 770,000 children.
Characterized by central DI, diabetes mellitus, optic atrophy, and deafness.
In this disorder, central DI is caused by the loss of ADH-secreting neurons in the supraoptic nucleus and impaired processing within the hypothalamus.
Congenital.
Often associated with midline craniofacial defects such as holoprosencephaly and septo-optic dysplasia.
Acquired.
Can result from damage to the pituitary gland or posterior hypothalamus from neurosurgery, trauma, tumors or other brain lesions, meningitis, or encephalitis.
May be either a temporary or a permanent disorder depending on the injury.
Nephrogenic DI.
Congenital.
Typically X-linked recessive involving mutations of VR2 or AQP2.
Acquired.
Variety of conditions that lead to the inability of the kidneys to respond to ADH.
Chronic renal failure.
Renal tubulointerstitial diseases.
Hypercalcemia.
Potassium depletion.
Sickle cell disease.
Medication-induced from drugs, including alcohol, lithium, diuretics, amphotericin B, demeclocycline.
Dietary abnormalities.
Primary polydipsia.
Decreased sodium chloride intake.
Severe protein restriction or depletion.
Nephrogenic DI that results from a metabolic condition may be reversed if the medication is stopped or the metabolic condition is corrected.
Clinical Presentation
Polyuria.
Dilute urine.
Polydipsia.
Inappropriately low urine sodium and osmolality.
Urine specific gravity <1.005.
Hypernatremia.
Serum hypo-osmolality.
Dehydration.
Diagnostic Evaluation
History and differential diagnoses.
The primary causes of polyuria and polydipsia are diabetes mellitus and central DI.
Other causes include urinary tract infection, relief of renal obstruction, and psychogenic polydipsia (characterized by excessive water intake).
Once hyperglycemia has been excluded, history should include age of initiation and rate of onset of polyuria (will reflect primary vs. secondary cause).
Serum laboratory studies.
Sodium >150 mEq/L.
Osmolality ≥295 mOsm/kg.
Urinary laboratory studies.
Sodium <30 mEq/L.
Osmolality <200 mOsm/L.
Specific gravity <1.005.
Brain imaging studies.
Head CT/MRI.
Presence of intracranial mass, abnormal findings of hypothalamic/pituitary stalk.
Water deprivation testing.
Only performed in acute care setting under close medical monitoring and supervision.
Fluids are restricted until as much as 5% of body weight has been lost to evaluate urinary response when the serum osmolality exceeds 295 mOsm/kg.
Central DI.
Concentrated urine and decreased urine output following ADH administration.
Nephrogenic DI.
Excessive, dilute urine despite hypernatremia and hyperosmolality.
Management
Restore hemodynamics.
Replace water deficits and correct electrolyte disturbances.
Decrease urine output to within normal range (e.g., vasopressin, desmopressin).
Treat underlying condition, when possible.
Volume replacement.
Maintenance IV fluids, plus mL per mL urine output replacement (usually allow 1-2-mL/kg/hour urine output and replace the remainder).
Monitor serum sodium closely.
Primary plan for central DI is ADH replacement to control polyuria.
ADH preparation depends on acuity of illness and the ability of the patient to tolerate oral intake.
Dose varies based on the preparation/formulation and include:
Vasopressin.
Continuous IV infusion.
Used in the critical care or perioperative setting due to its short half-life (10-20 minutes) and easy titration.
Initiated at a dose of 0.5 milliunits/kg/hour and titrated until urine output is decreased.
Titrated to obtain urine output less than 4 mL/kg/hour.
Desmopressin.
Used in all other settings.
Available in oral and intranasal formulations.
Chronic therapy: Dose range is 5 to 30 µg/day, with a peak effect within 1 to 5 hours.
Nephrogenic DI is resistant to vasopressin administration (Figure 7.2).
 FIGURE 7.2 • Diabetes Insipidus Flowchart. |
PEARL
Pediatric patients with a known history of DI who are acutely ill may quickly develop signs of dehydration or hypovolemic shock.
Diabetic Ketoacidosis
Keshava Gowda
Tageldin M. Ahmed
Background/Definition
Potentially life-threatening complication of type 1 diabetes.
Stimulated by insulin deficiency.
Insulin must be present to bind to receptor sites, allowing glucose to enter cells.
Without insulin, the body breaks down fat for fuel, resulting in ketosis.
Diabetic ketoacidosis (DKA) is diagnosed when blood glucose is >200 mg/dL, presence of serum ketones (ketonemia), urine ketones (ketonuria), blood pH <7.3, and serum bicarbonate <15 mmol/L.
Epidemiology/Etiology
Previous diagnosis of type I diabetes:
Insulin dose omission.
Intercurrent illness.
Stress increases counterregulatory hormone levels, promoting gluconeogenesis and insulin resistance.
Unrecognized disruption in insulin pump therapy (if applicable).
New onset of type diabetes
Clinical Presentation
Polyuria, polydipsia, polyphagia, abdominal discomfort/pain, nausea and vomiting, nonspecific weakness, fruity breath odor, Kussmaul respirations.
Severe presentation can include altered mental status, seizures, and coma.
Physical Examination Findings
Tachycardia.
Decreased pulses.
Poor perfusion.
Dry mucus membranes.
Enophthalmos.
Poor skin turgor.
Hypotension.
Deep or labored breathing.
Diagnostic Evaluation
Blood glucose >200 mg/dL, serum pH <7.3, bicarbonate <15 mmol/L.
Serum electrolytes, blood urea nitrogen (BUN), creatinine, calcium, magnesium, phosphorus.
High serum osmolality.
Positive serum/urine ketones.
Hemoglobin A1C.
Complete blood count with differential.
Leukocytosis is not a reliable marker of infection.
Elevation in stress hormones may mimic infection.
Autoimmune markers.
GAD-65 (glutamic acid decarboxylase), IA-2, IA-2β.
Insulin auto-antibodies.
May be evaluated for evidence of associated autoimmune conditions.
Management
Monitoring.
Cardiac monitoring.
Assess T wave alterations with hyper- or hypokalemia.
Cerebral edema.
Most serious complication and frequent cause of death.
Survivors often experience neurologic sequelae.
Occurs in approximately 1% of cases.
Has been reported prior to the initiation of therapy, but typically occurs after the start of treatment.
Risk factors.
Young age.
New-onset diabetes.
Longer duration of symptoms.
Signs and symptoms of cerebral edema (see Section 6: Neurologic Disorders).
Requires rapid recognition and treatment.
Elevate head of bed.
Administer hyperosmolar therapy.
Preferred treatment is hypertonic saline (e.g., 3% saline).
5 to 10 mL/kg.
Mannitol.
0.5 to 1 g/kg IV.
May be repeated if no response.
Intubation and mechanical ventilation if progression of symptoms.
Head CT is not routinely completed prior to start of therapy, but can be obtained to evaluate and document presence of cerebral edema.
Respiratory support.
Supplemental oxygen.
If respiratory distress, circulatory impairment, or shock.
If altered mental status, consider mechanical ventilator support.
Access.
Establish multiple peripheral IV catheters.
May require arterial line for frequent laboratory sampling.
Judicious fluid replacement.
Avoid overaggressive fluid replacement with frequent evaluation and repeated boluses, as needed.
Moderate to severe DKA with poor perfusion.
Start with 0.9 normal saline (NS) 10 to 20 mL/kg bolus.
Repeat bolus if poor perfusion/hypotension persists.
Obtain repeat blood gas, finger-stick glucose, and basic metabolic panel after initial fluid resuscitation.
Remaining fluids are calculated deficits and replaced over 36 to 48 hours using isotonic fluid (e.g., 0.9 NS).
Subtract the volume administered in boluses from 24 hours fluid calculation.
Withhold potassium from fluids until evidence of adequate kidney function and serum potassium level decreasing.
Consider use of two-bag method when ready for introduction of glucose.
Allows regulation of glucose from D5W to D10W.
Equal electrolyte supplements are added to each bag when using two-bag method.
Add dextrose to IV fluids when blood glucose level is 200 to 250 mg/dL.
Adjust glucose to prevent rapid drop in blood glucose (e.g., >100 mg/dL/hour).
Insulin therapy.
Insulin infusion is typically started at 0.1 unit/kg/hour.
Follow hourly blood glucose levels.
Adjust the amount of dextrose in the IV fluids rather than decreasing the insulin.
Decrease the insulin infusion only in cases when patient demonstrates extreme sensitivity to insulin (e.g., usually young children).
Continue the infusion until the pH is >7.3 and bicarbonate level >18 mmol/L, or ketonemia has resolved.
Sodium.
Replace using 0.9 NS or Ringer lactate for first several hours of DKA therapy.
Follow this initial therapy with 0.45 NS.
Hyperglycemia results in a lower serum sodium concentration.
Results in dilutional hyponatremia, due to the movement of water into the extracellular fluid.
Calculation:
Corrected Sodium = [Na+] + [1.6 × (plasma concentration mg/dL – 100)]/100
As hyperglycemia improves, serum sodium should improve.
If sodium level increases or does not begin to fall, there is concern for the development of cerebral edema.
Potassium.
Serum potassium levels may be low, normal, or high in DKA presentation.
Potassium loss is an effect of movement of water out of the cells due to the increase in serum osmolarity, resulting in concentrated potassium level.
Add potassium to IV fluid when potassium level <6 mEq/L, based on institutional protocol.
Correction of hyperglycemia and administration of insulin result in shift of potassium back into the cells, evidenced by a decrease in serum potassium.
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