OVERVIEW: What every practitioner needs to know

Are you sure your patient has counter-regulatory hormone deficiency? What are the typical findings for this disease?

Glucagon, epinephrine, cortisol and growth hormone (GH) raise plasma glucose concentration and are referred to as glucose counterregulatory hormones. Hypoglycemia due to deficiency of GH and/or cortisol most commonly occurs in neonates and children less than 5 years of age, but may also occur in older children and adults when food intake is limited; e.g., when an illness results in anorexia and/or vomiting or when the patient is fasted prior to undergoing a procedure.

Deficiency of GH and/or cortisol should always be considered in the differential diagnosis of non-hyperinsulinemic hypoglycemia. Measurement of serum GH and cortisol concentrations should routinely be included in the so-called “critical sample” obtained at the time of spontaneous hypoglycemia. Elevated levels exclude deficiency, whereas random values that are not clearly elevated do not rule out the possibility of deficiency and a formal evaluation of GH or cortisol secretion will be required to definitively rule out GH or cortisol deficiency.

The hormones that raise the plasma glucose concentration are referred to as glucose counterregulatory hormones. These include glucagon, epinephrine, cortisol and growth hormone (GH). These hormones are involved in the prevention as well as the correction of hypoglycemia. Glucagon and epinephrine are important for the immediate restoration of the blood glucose concentration.

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Although GH and cortisol are released immediately in response to hypoglycemia, their counterregulatory effects do not become manifest for several hours. In adults, the glycemic thresholds for activation of glucose counterregulatory hormones lie within or just below the physiological blood glucose concentration and are slightly higher than the threshold for symptoms.

Because there are redundant glucose counterregulatory mechanisms, hypoglycemia caused by deficiency of counterregulatory hormones is uncommon. Deficiency of glucagon or epinephrine is extremely rare. GH and/or cortisol deficiency more commonly cause hypoglycemia, which results from decreased gluconeogenesis and increased glucose utilization (owing to increased tissue sensitivity to insulin in the absence of GH and cortisol).

Whereas the vast majority of adults with GH and/or cortisol deficiency do not develop hypoglycemia, deficiency of these hormones not infrequently causes hypoglycemia in neonates and in children less than 5 years of age. Isolated cortisol deficiency can cause fasting hypoglycemia throughout childhood. This observation suggests that cortisol, GH, or both play a more important role in the physiology of glucose counterregulation during fasting in infancy and early childhood than at an older age. Susceptibility to fasting hypoglycemia is greatest in but not confined to young children who are deficient in both GH and cortisol.

Hypoglycemia in infants and children with cortisol deficiency, GH deficiency, or both is generally preceded by a period of calorie deprivation, often the result of a delay in feeding or an intercurrent illness.

In adults, hypoglycemia is not a feature of the epinephrine deficient state that results from bilateral adrenalectomy when glucocorticoid replacement is adequate; nor does hypoglycemia occur during pharmacological blockade of catecholamine actions when other glucoregulatory systems are intact.

In children, there is a lack of data concerning the role of epinephrine deficiency in the pathogenesis of hypoglycemia. Reduced urinary and plasma epinephrine responses to insulin-induced hypoglycemia have been described in patients with ketotic hypoglycemia of childhood. The significance of this observation is unclear.

Isolated glucagon deficiency would be expected to result in lower fasting plasma glucose concentrations but not hypoglycemia if epinephrine secretion were intact and insulin secretion were appropriately suppressed. Neonatal hypoglycemia has, rarely, been attributed to glucagon deficiency. However, these reports are unconvincing and hypoglycemia may have been due to hyperinsulinism in which a blunted glucagon response to hypoglycemia has been described.

Pituitary disorders

Combined GH and ACTH deficiencies may occur in congenital or acquired disorders of pituitary function.

Congenital hypopituitarism may present with life-threatening hypoglycemia, hyponatremia, shock and microphallus and/or cryptorchidism. Other congenital malformations (cleft lip and/or palate) can also be associated with hypopituitarism. Hypoglycemia from anterior hypopituitarism may be a cause of sudden death. Growth failure becomes apparent later in childhood. The causes of congenital hypopituitarism are shown in Table I.

Table I.n

Causes of Congenital Hypopituitarism

Acquired hypopituitarism may result from tumors (most common is craniopharyngioma), radiation, infection, hydrocephalus, trauma (including injury from surgery), vascular anomalies.

GH deficiency is characterized by low serum IGF-1 and IGFBP-3 concentrations and low GH levels in response to pituitary stimulation with GH secretagogues such as arginine, clonidine, glucagon, insulin-induced hypoglycemia. Depending on the specific cause of GH deficiency, a cranial MRI may show an abnormality of the pituitary gland.

Primary adrenocortical insufficiency should be considered when there is a history of lack of appetite, unexplained fatigue, muscle weakness, nausea, vomiting, weight loss, salt craving, fasting hypoglycemia, hypotension, and increased skin pigmentation that cannot be explained by sun exposure.

Patients with both glucocorticoid and mineralocorticoid deficiency typically present with fasting hypoglycemia, hyponatremia, hyperkalemia, metabolic acidosis (with normal anion gap), low serum cortisol and markedly increased concentration of plasma ACTH and plasma renin activity (PRA). Other clinical and biochemical features depend on the specific cause of primary adrenocortical insufficiency.

Secondary adrenocortical insufficiency (ACTH deficiency) should always be considered when there is a history of glucocorticoid therapy (including topical steroid therapy, inhaled and intralesional injection of glucocorticoids) and in patients with other known pituitary hormone deficiencies.

If the dose of glucocorticoid administered was greater than required for physiological replacement then there may be adrenocortical suppression. If the duration of therapy was less than 4 weeks, suppression will be transient and recovery will be prompt. If the duration of therapy was more than 4 weeks, suppression will last for 1 week to 6 months. In these patients, it would be appropriate to resume glucocorticoid replacement in cases of stress for up to 6 months after cessation of treatment.

Patients with ACTH deficiency have glucocorticoid deficiency without mineralocorticoid deficiency. They present with fasting hypoglycemia and may have mild hyponatremia, but do not have hyperkalemia or metabolic acidosis. Both serum cortisol and plasma ACTH concentrations are low.

Primary adrenocortical insufficiency should be considered when there is a history of unexplained anorexia, fatigue, salt craving. Other symptoms include nausea and vomiting, abdominal pain, diarrhea, weakness, weight loss, apathy and confusion. Examination findings include dehydration, hypovolemia and tachycardia, postural hypotension, increased skin pigmentation. Characteristic laboratory abnormalities are hypoglycemia, hyponatremia, hyperkalemia, metabolic acidosis. The electrocardiogram shows low voltages and chest X-ray shows a small cardiac silhouette.

Secondary adrenocortical insufficiency must always be considered when any of the above symptoms and signs are evident in a patient who has received prolonged (more than 1 week) treatment with glucocorticoids and in patients with other known pituitary hormone deficiencies.

GH deficiency should be considered in an infant or child with a central midline defect, single central incisor, a male infant with a microphallus and/or cryptorchidism; slow linear growth.

What other disease/condition shares some of these symptoms?

As compared with acute hypoglycemia induced by insulin infusion (e.g., an insulin tolerance test), GH and cortisol respond differently to spontaneous hypoglycemia. The difference may be attributable to the slower rate of fall of the blood glucose concentration in the development of spontaneous hypoglycemia.

Infants with hyperinsulinemic hypoglycemia may mount a suboptimal cortisol response to hypoglycemia, which can cause difficulty interpreting a low serum cortisol concentration obtained at the time of hypoglycemia. In these circumstances, a cosyntropin (synthetic ACTH) stimulation test is useful to determine the significance of the low serum cortisol value in an infant with hypoglycemia.

What caused this disease to develop at this time?

The causes of congenital pituitary disorders are shown in Table I.

Adrenal disorders include adrenal dysgenesis or hypoplasia, impaired steroidogenesis, and adrenal destruction. The causes of adrenal insufficiency are shown in Table II.

Table II.n

Causes of adrenal insufficiency

Adrenal dysgenesis or hypoplasia includes a sporadic form associated with pituitary hypoplasia, an autosomal recessive form, an X-linked form, and a number of forms caused by ACTH resistance. These disorders are likely to present in the first few months of life.

Deficiency of steroidogenic factor-1 (SF-1), an intracellular transcription factor encoded by the NR5A1 (nuclear receptor subfamily 5, group A, member 1) geneon chromosome 9q33, can lead to adrenal failure with complete XY sex reversal due to testicular dysgenesis. In females, the ovaries may be spared.

Congenital X-linked adrenal hypoplasia is caused by mutations in NR0B1 (nuclear receptor, subfamily 0, group B, member 1), also known as DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1). The gene, located on Xp21.3, encodes the nuclear receptor protein, DAX1.Mutations in NR0B1/DAX1 lead to failure of the definitive adrenal cortex to form. Approximately 50% of males present in the first few months of life, whereas the remaining boys present more insidiously later in childhood. Expression of DAX-1 is important for development of gonads, adrenal cortex, hypothalamus and the pituitary gland. The condition is also associated with hypogonadotropic hypogonadism. Loss of this gene may be part of a contiguous gene deletion syndrome with NR0B1/DAX-1 and glycerol kinase deficiency and, occasionally, Duchenne muscular dystrophy.

Familial glucocorticoid deficiency is a rare autosomal recessive disorder characterized by a failure of cortisol production owing to adrenal ACTH resistance.

AAA syndrome occurs in males and females and should be considered when glucocorticoid deficiency occurs with other features including achalasia, alacrima, and autonomic neuropathy in association with hyperpigmentation.

Impaired steroidogenesis:

Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is one of the most common autosomal recessive disorders in humans (estimated carrier frequency of deleterious mutations is 1 in 50; incidence is 1 in 15,000 live births).

The CAH phenotype reflects the degree of 21-hydroxylase enzyme deficiency. Complete enzyme deficiency with impairment of both cortisol and aldosterone synthesis results in the salt-wasting form characterized by prenatal virilization of females and salt-wasting crises in the neonatal period. Partial enzyme deficiency leads to simple virilizing CAH characterized only by prenatal virilization in females and pseudo-precocious puberty in males and females. The first clue to the condition in a male infant may be collapse in the first 1-8 weeks of life with hypoglycemia, hypotension, hyponatremia and hyperkalemia. Other causes of impaired steroidogenesis are much less common.

Adrenal destruction:

Approximately 50% of cases of adrenal failure are caused by autoimmune destruction and can be associated with failure of other endocrine organs in the autoimmune polyglandular syndromes (APS): APS-1 (mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency); APS-2 (autoimmune thyroid disease, type 1 diabetes mellitus, adrenal insufficiency).

X-linked adrenoleukodystrophy (ADL) occurs in males and is confirmed by the detection of abnormal serum levels of very long chain fatty acids.

Adrenal destruction from hemorrhage or ischemia occurs in severe systemic illness such as neonatal hypoxia or meningococcal septicemia.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Plasma counterregulatory hormone concentrations should be measured during spontaneous hypoglycemia by obtaining a so called “critical sample.”

Elevated levels (GH >7.5 ng/mL and cortisol >18 mcg/dL) exclude deficient secretion. However, a seemingly low cortisol concentration measured during spontaneous hypoglycemia is not sufficient evidence to prove adrenocortical insufficiency because of the effect of recurrent hypoglycemia to shift glycemic thresholds for cortisol secretion to lower plasma glucose concentrations. Likewise, GH secretion in response to spontaneous hypoglycemia is not a good measure of GH reserve. Further specific testing will be necessary if the “critical sample” values do not rule out GH or cortisol deficiency.

GH and cortisol respond differently to spontaneous hypoglycemia as compared with hypoglycemia induced by insulin infusion (e.g., an insulin tolerance test), which may be attributable to the slower rate of fall of the blood glucose concentration.

Infants with hyperinsulinemic hypoglycemia may mount a suboptimal cortisol response to hypoglycemia, which can cause difficulty interpreting a low serum cortisol concentration obtained at the time of hypoglycemia. In these circumstances, a cosyntropin stimulation test is useful to determine the significance of the low serum cortisol value.

GH and cortisol concentrations obtained at the time of hypoglycemia in children undergoing fasting tests are frequently below the thresholds considered to be normal. A large percentage of children would erroneously be diagnosed as having adrenal insufficiency or GH deficiency on the basis of the critical sample alone. Fasting is not a potent stimulus for GH secretion and even in fasting children who do not develop hypoglycemia, GH levels frequently are <7.5 ng/mL.

Primary adrenocortical insufficiency is characterized by a low serum cortisol together with a markedly increased plasma ACTH concentration. In addition, as a consequence of aldosterone (mineralocorticoid) deficiency, there is a characteristic serum electrolyte pattern with low sodium and chloride, increased potassium and low bicarbonate concentrations consistent with metabolic acidosis. Urinary sodium concentration is increased (>20 mmol/L) and plasma renin activity (PRA) is increased in patients with aldosterone deficiency.

In secondary adrenocortical insufficiency (ACTH deficiency), aldosterone is not deficient; hence hyperkalemia and metabolic acidosis do not occur. However, hyponatremia may be present owing to cortisol deficiency (as cortisol is required for normal free water clearance). PRA levels are usually normal.

To confirm suspected primary adrenocortical insufficiency, perform a rapid ACTH test. Measure the serum cortisol response to synthetic ACTH (cosyntropin test). Blood samples for serum cortisol and plasma ACTH determination are obtained immediately before IM or IV administration of cosyntropin (Cortrosyn; 15 mcg/kg in neonates, 125 mcg up to 2 years, 250 mcg over 2 years) and serum cortisol is measured 60 minutes after injection. A serum cortisol value at 60 minutes that is 7-10 mcg/dL above the baseline level or is ≥18 mcg/dL is considered to be normal.

In patients with suspected secondary adrenocortical insufficiency, the “low dose” 1 mcg per meter2 cosyntropin stimulation test in which serum cortisol is measured before and 30 minutes after the test dose is more sensitive than the “high dose” for detecting mild degrees of secondary adrenocortical insufficiency caused by abnormality of the hypothalamus-pituitary-adrenal axis.

To confirm suspected GH deficiency, measure the serum GH response to a GH secretagogue, (e.g., arginine, clonidine, glucagon, insulin-induced hypoglycemia), ideally, after priming with estrogen. If the clinical situation permits, the most robust test to assess counterregulation is to measure the response to insulin-induced hypoglycemia (insulin tolerance test). This test is performed less frequently because it is unpleasant for patients and requires continuous observation by a physician. Clinical evidence of severe hypoglycemia must be promptly treated with intravenous glucose.

The insulin tolerance test is performed after an overnight fast. Plasma glucose, cortisol, and GH concentrations are measured before administration of insulin and at 15-30 minute intervals for 2 hours after rapid intravenous injection of regular insulin (0.05-0.1 unit per kg body weight). In addition, plasma glucagon and epinephrine levels can be measured (though difficult to justify since isolated deficiencies of glucagon or epinephrine would not be expected to cause clinical hypoglycemia and combined deficiencies of glucagon and epinephrine secretion have been documented only in type 1 diabetes mellitus). An insulin tolerance test should not be performed in infants or in children with a seizure disorder.

In the patient suspected of having GH and/or ACTH deficiency, first confirm normal thyroid function. If the patient has central (secondary or pituitary) hypothyroidism, first restore a euthyroid state before performing functional tests of the pituitary or adrenal gland.

In the patient with suspected autoimmune adrenalitis, positive anti-adrenal 21-hydroxylase autoantibodies confirm the diagnosis.

The patient with adrenal insufficiency due to adrenoleukodystrophy has increased plasma very long chain fatty acid concentrations.

Would imaging studies be helpful? If so, which ones?

Cranial MRI should be obtained to examine the pituitary gland in the patient with isolated GH deficiency or multiple anterior pituitary hormone deficiencies.

MRI may demonstrate atrophy of the optic chiasm and absence of the septum pellucidum, classical signs of septo-optic dysplasia.

Confirming the diagnosis

See Figure 1 for a diagnostic algorithm to evaluate patients with suspected adrenal insufficiency.

Figure 1.n

If you are able to confirm that the patient has counter-regulatory hormone deficiency, what treatment should be initiated?

An adrenal crisis, often precipitated by stress (infection, surgery, trauma) is characterized by vomiting, dehydration, fever, hypoglycemia, hypotension, shock, coma.

Shock is treated by rapid volume expansion (20 mL per kg normal saline IV).

Hypoglycemia is treated with an IV infusion of 0.3 gram per kg dextrose over 5 to 10 minutes, followed by 0.5 gram per kg per hour.

Hydrocortisone sodium succinate, 50 to 100 mg, is given as an IV bolus; then, hydrocortisone 100 mg per meter2 per day is given as a continuous infusion, gradually reducing the dose to maintenance over 3 to 5 days and changing to oral therapy when appropriate.

Maintenance therapy consists of hydrocortisone and fludrocortisone replacement and ad lib table salt. Physiologic cortisol secretion is approximately 7-9 mg per meter2 per day in neonates and 6-8 mg per meter2 per day in children and adolescents. The dose of hydrocortisone is given in three divided doses with a larger dose in the morning. The usual dose of fludrocortisone (Florinef) is 0.05 mg to 0.1 mg per day; some infants require up to 0.2 mg per day.

During periods of severe stress the hydrocortisone dose should be temporarily increased to 50 to 100 mg per meter2 per day (depending on severity) and the frequency of administration increased to every 6 hours. Parents should know how to administer intramuscular hydrocortisone sodium succinate (SoluCortef) in an emergency, which will provide up to 6 hours of coverage. Specially formulated hydrocortisone rectal suppositories in a wax base (prepared by a compounding pharmacist) are an acceptable alternative when parents are reluctant to give an injection. The recommended dose is 100 mg per meter2 per dose per rectum. This route is often more acceptable to patients and parents than intramuscular injections.

Patients should wear an identification tag indicating they have adrenal insufficiency.

GH deficiency is treated by a daily injection of human growth hormone, typically administered SC at bedtime. The usual dose is in the range 0.025 to 0.05 mg per kg per day. Associated anterior pituitary hormone deficiencies may require replacement of the deficient hormones; for example, TSH deficiency is treated by replacing levothyroxine, and ACTH deficiency by replacing cortisol (see above).

What is the evidence?

Bornstein, SR. “Predisposing factors for adrenal insufficiency”. N Engl J Med. vol. 360. 2009. pp. 2328-2339. (This is a comprehensive review of the causes of adrenal insufficiency and includes recommendations for diagnosis and treatment.)

Hussain, K, Hindmarsh, P, Aynsely-Green, A. “Spontaneous hypoglycemia in childhood is accompanied by paradoxically low serum growth hormone and appropriate cortisol counterregulatory hormonal responses”. J Clin Endocrinol Metab. vol. 88. 2003. pp. 3715-3723. (The serum GH and cortisol responses to spontaneous hypoglycemia in 22 children were compared with those of 16 children undergoing an insulin tolerance test (ITT) for diagnostic purposes. This study shows that the mechanism(s) of the serum GH response to spontaneous hypoglycemia is different from that due to acute hypoglycemia induced by administration of intravenous insulin. A low GH level detected at the time of spontaneous hypoglycemia does not necessarily imply GH deficiency or GH as a cause of the hypoglycemia.)

Kelly, A, Tang, R, Becker, S, Stanley, CA. “Poor specificity of low growth hormone and cortisol levels during fasting hypoglycemia for the diagnoses of growth hormone deficiency and adrenal insufficiency”. Pediatrics. vol. 122. 2008. pp. e522-e528. (This review of 151 diagnostic fasting studies in 84 children (age range 2 days to 14.3 years) showed that a single low growth hormone (GH, <7.5 ng/mL) or cortisol (<18 mcg/dL) value at the time of fasting hypoglycemia has poor specificity for the respective diagnoses of GH and adrenal insufficiency.)

Hsieh, S, White, P. “Presentation of primary adrenal insufficiency in childhood”. J Clin Endocrinol Metab. vol. 96. 2011. pp. E925-E928. (Retrospective review of children with adrenal insufficiency identified in 1999-2010 at a tertiary care pediatric hospital. Hypoglycemia was documented in four of 15 patients in whom it was sought.An important finding was that hyperkalemia is not a consistent finding).