Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 3-4

Ten-Year-Old Girl

AMY FELDMAN

HISTORY OF PRESENT ILLNESS

The patient is a 10-year-old Caucasian female who presents with vomiting. She was in her usual state of health until 5 days ago when she developed nonbloody nonbilious emesis 5-7 times per day. She complains of a 2-day history of weakness, dizziness, and lethargy. She also admits to anorexia, decreased urine output, and a 5-pound weight loss during the past week. She denies fever, diarrhea, abdominal pain, rash, joint pain, or dysuria.

MEDICAL HISTORY

The patient has a history of mild intermittent asthma but has never required steroids or hospitalization. She uses albuterol intermittently but is not on any maintenance asthma medications. Her family history is negative for autoimmune diseases or gastrointestinal diseases.

PHYSICAL EXAMINATION

T 37.8°C; RR 28/min; HR 138/min; BP 108/53 mmHg

Weight (22.9 kg) 5th percentile; Height (150 cm) 95th percentile

Physical examination revealed a lean female in no acute distress. She had dry mucous membranes and there were numerous hyperpigmented macules scattered about the buccal surface of her mouth and on her tongue (see Figure 3-8). Her cardiovascular examination revealed tachycardia but she had normal rhythm and good peripheral pulses. Her pulmonary examination was normal. Her abdomen was soft, nontender, and nondistended without any hepatosplenomegaly or palpable masses. Neurologic examination was grossly normal. Her skin appeared slightly bronzed.

Image

FIGURE 3-8. Skin and mucosal changes seen in primary adrenal insufficiency. (Reproduced, with permission, from Strange GR, Ahrens WR, Schafermeyer RW, Wiebe RA, eds. Pediatric Emergency Medicine. 3rd ed. New York: McGraw-Hill; 2009.)

DIAGNOSTIC STUDIES

Laboratory evaluation revealed a normal complete blood count. Serum chemistries were as follows: sodium, 123 mEq/L; potassium, 6.6 mEq/L; chloride, 95 mEq/L; bicarbonate, 14 mEq/L; blood urea nitrogen, 55 mg/dL; creatinine, 2.4 mg/dL; glucose, 40 mg/dL; calcium, 8.1 mg/dL; phosphorus, 5.2 mg/dL; and urinary sodium, 30 mEq/L. Urinalysis was notable for a specific gravity of 1.020 and three plus ketones. A venous blood gas had a pH of 7.25.

COURSE OF ILLNESS

The patient was admitted to the hospital and was given a normal saline bolus followed by an infusion of dextrose containing fluids. On further questioning, her mother reported that she had a 1-year history of salt craving and had recently developed dark spots on her body (see Figure 3-8). Based on the history, physical examination, and laboratory studies, she was given a presumptive diagnosis and was started on appropriate therapy.

DISCUSSION CASE 3-4

DIFFERENTIAL DIAGNOSIS

Patients who present with acute renal failure should first be categorized as having prerenal, renal, or postrenal azotemia. Prerenal azotemia is due to decreased renal perfusion secondary to hypovolemia, hypotension, hypoalbuminemia, or cardiac failure. Intrinsic acute renal failure is characterized by renal parenchymal damage and can be secondary to vascular dysfunction (renal vein thrombosis, hemolytic uremic syndrome, vasculitis), glomerular dysfunction (poststreptococcal, Henoch-Schönlein purpura, Lupus), or tubular dysfunction (acute tubular necrosis, interstitial nephritis, tumor lysis syndrome, drug-induced nephritis). Postrenal azotemia occurs secondary to obstruction of the urinary tract (posterior urethral valves, urolithiasis, hemorrhagic cystitis, tumor).

This patient’s history of emesis and decreased oral intake, her physical examination of dry mucous membranes and weight loss, and her urinalysis with a high specific gravity and 3 plus ketones all suggest hypovolemic prerenal azotemia. Hypovolemia can occur from hemorrhage, vomiting and diarrhea, third spacing, or adrenal disease. Given the laboratory findings of hyperkalemia, hyponatremia, hypoglycemia, and high urine sodium, an adrenal etiology was suspected.

DIAGNOSTIC TESTS

Diagnosis of primary adrenal insufficiency begins with a basic metabolic panel that shows hypoglycemia, hyponatremia, and hyperkalemia. A 24-hour urine collection can be useful to look for high urinary excretion of sodium and low urinary excretion of potassium. The most definitive test for primary adrenal insufficiency is measurement of serum levels of cortisol before and after administration of ACTH. In primary adrenal insufficiency, resting levels of cortisol are low and do not increase normally after administration of ACTH.

DIAGNOSIS

This patient’s histories of vomiting, anorexia, weight loss, salt craving, and hyperpigmentation were all suggestive of primary adrenal insufficiency (see Table 3-6). Laboratory data of low serum sodium, glucose and bicarbonate, and elevated potassium and blood urea nitrogen were also consistent with the diagnosis. The patient underwent an ECG to ensure that her hyperkalemia was not causing cardiac abnormalities. The patient then underwent an ACTH stimulation test. Evaluation of the patient’s blood obtained prior to administering ACTH revealed a low serum cortisol level and a high ACTH level. After receiving ACTH, the patient failed to mount a cortisol response confirming the diagnosis of primary adrenal insufficiency. She was started on appropriate glucocorticoid and mineralocorticoid IV replacement during hospitalization, which resulted in normalization of all of her labs. She was discharged home on oral hydrocortisone and Florinef.

TABLE 3-6 Signs and symptoms of primary adrenal insufficiency.

Glucocorticoid Deficiency

Hypoglycemia

Increased insulin sensitivity

Ketosis

Decreased cardiac output, decreased vascular tone, hypotension

Nausea, fatigue, headaches

Hyperpigmentation

Mineralocorticoid Deficiency

Dehydration and weight loss

Hypovolemia

Hypotension

Hyponatremia, hyperkalemia, acidosis

Hyperreninemia

Salt craving

Androgen Deficiency

Absence of secondary sexual characteristics

Decreased pubic and axillary hair

Decreased libido

INCIDENCE AND EPIDEMIOLOGY OF ADRENAL INSUFFICIENCY

Adrenal insufficiency can be primary or secondary in nature. In primary adrenal insufficiency (Addison disease), there is decreased or absent production of all three groups of adrenal steroid hormones. Primary adrenal insufficiency is uncommon and is estimated to affect 90 to 140 per 1 million people. Primary adrenal insufficiency can occur congenitally, or can develop later in life secondary to autoimmune destruction of the adrenal cortex, bilateral adrenal hemorrhage, adrenal degeneration (adrenoleukodystrophy), or adrenal injury from trauma, thrombosis, tumor, or infection (e.g., tuberculosis, meningococcemia).

The most likely etiology of primary adrenal insufficiency depends on the patient’s age. At birth, the most common cause of adrenal insufficiency is adrenal hemorrhage from a perinatal event. In infants, congenital adrenal hyperplasia (CAH) is the most likely cause of adrenal insufficiency. In older children and adults living in developed countries, autoimmune destruction of the adrenal cortex is the most common cause of insufficiency. Forty-five percent of patients with autoimmune induced adrenal insufficiency have another autoimmune endocrinopathy or have autoimmune polyglandular syndrome. Type I autoimmune poly-glandular syndrome is an autosomal recessive disorder resulting from mutation in the AIRE gene. It can result in chronic mucocutaneous candidiasis, ectodermal dysplasia, hypoparathyroidism, and Addison’s disease. Type II autoimmune polyglandular syndrome can result in thyroid disease, Type I diabetes, and Addison disease.

Secondary adrenal insufficiency is more common and affects 150 to 280 per 1 million people. Secondary adrenal insufficiency is caused by lack of corticotropin-releasing hormone (CRH) or lack of adrenocorticotropic hormone (ACTH). These deficiencies may be the result of congenital abnormalities of the pituitary or hypothalamus, or may arise secondary to chronic steroid use or destruction of the pituitary/hypothalamus by infection, tumor, hemorrhage, or irradiation.

CLINICAL PRESENTATION

Primary adrenal insufficiency results in cortisol and aldosterone deficiency. As a result of these deficiencies, patients present with dehydration, hypoglycemia, hyperkalemia, ketosis, hypotension, and eventual shock.

The clinical presentation of a child with adrenal insufficiency depends on the age of the child and the etiology of the disease. Newborns and young infants often present in shock. They become ill during the course of a few days, and present with severe electrolyte abnormalities. Infants often will not have ketosis due to immature kidneys. In older children, adrenal insufficiency is often more insidious, taking several weeks or months to manifest. Older children present with muscle weakness, fatigue, anorexia, weight loss, emesis, and hypotension. Hyperkalemia may not be present initially.

Older children with primary adrenal insufficiency can develop hyperpigmentation, particularly on their skin, genitalia, and gingival and buccal mucosa. Hyperpigmentation results from cortisol deficiency. Without appropriate cortisol, there is decreased negative feedback on the hypothalamus and pituitary leading to increased secretion of ACTH and melanocyte-stimulating hormone. Infants usually do not display hyperpigmentation as this sign takes longer to develop.

The most worrisome presentation of primary adrenal insufficiency is the child who presents in adrenal crisis. These patients present in a shock-like state with labored breathing, hypotension, confusion, lethargy, and coma. Adrenal crisis is typically precipitated by an antecedent infection or bodily stress during which the body is unable to mount an adequate glucocorticoid response. This may occur in undiagnosed patients, or in previously diagnosed patients taking inadequate amounts of replacement therapy. In the absence of immediate and intensive therapy, the course can be rapidly fatal.

In patients with secondary adrenal insufficiency, there is no deficiency of mineralocorticoids. As a result, these patients present with fatigue, headaches, weakness, or hypotension but do not usually have electrolyte abnormalities. Hyperpigmentation does not occur because ACTH levels are not elevated.

DIAGNOSTIC RATIONALE

Diagnosing a patient with adrenal insufficiency depends on having a high index of suspicion as symptoms can be similar to those seen with gastroenteritis and other acute infections. Patients presenting with hyponatremia and hyperkalemia, especially in the setting of hyperpigmentation, should be considered to have adrenal insufficiency until proven otherwise.

Serum electrolytes. Hyponatremia, hypoglycemia, and hyperkalemia occur as described above.

Urinalysis. 24-hour urine collection shows high urinary excretion of sodium and chloride and decreased excretion of potassium.

Serum cortisol. The most definitive test for adrenal insufficiency is measurement of serum cortisol levels before and after administering ACTH. In a patient with primary adrenal insufficiency, resting cortisol levels are low and do not increase after administration of ACTH.

Other serum studies. Antiadrenal antibodies and other autoantibodies can be sent if an autoimmune etiology is suspected.

Abdominal CT scan. CT scan can be helpful in evaluating for calcifications, hemorrhage, or infiltration of the adrenal glands.

TREATMENT

Acute adrenal insufficiency is a life-threatening emergency that requires immediate treatment for shock and electrolyte abnormalities. After airway and breathing have been secured, intravenous or intraosseous access must be obtained immediately. Resuscitation continues with normal saline to correct hypotension and hyponatremia, and glucose to correct hypoglycemia. If hyperkalemia is severe, one must perform an ECG and consider therapies such as calcium carbonate, bicarbonate, insulin, or potassium-binding resins as necessary. Glucocorticoid therapy must be given when the diagnosis of adrenal insufficiency is entertained. Immediate management consists of 50-100 mg of hydrocortisone IV. If possible, blood levels of ACTH, cortisol, aldosterone, renin, 17-alpha-hydroxyprogesterone, and adrenal androgens should be obtained prior to giving hydro-cortisone as steroids will change laboratory results. Mineralocorticoid therapy is not useful acutely because it takes several days for its sodium-retaining effects to occur. After the patient is stabilized, one must identify and treat the precipitating cause of the crisis if possible. Chronic therapy consists of daily replacement with hydrocortisone and fludrocortisone acetate (Florinef).

Patients with adrenal insufficiency need to be educated about their disease. Patients must understand the importance of increasing their hydrocortisone dose during periods of bodily stress. Every patient with primary adrenal insufficiency should wear a medical alert bracelet and carry stress dose steroids with them in case of an emergency.

SUGGESTED READINGS

1. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003; 361:1881-1893.

2. Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA. 2002;287:236-240.

3. Laron Z. Hypoglycemia due to hormone deficiencies. J Pediatr Endocrinol. 1998;11:s117-s120.

4. Schatz DA, Winter DE. Autoimmune polyglandular syndrome: clinical syndrome and treatment. Endocrinol Metabol Clin N Am. 2002;31:339-352.

5. Shulman DI, Palmert MR, Kemp SF. Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics. 2007;119:e484-e494.

6. Ten S, New M, Maclaren N. Clinical review 130: Addison’s disease. J Clin Endocrinol Metab. 2001;86:2909-2922.