Adrenal insufficiency - children

Module overview

Adrenal insufficiency is an endocrine condition defined as the inadequate production or action of glucocorticoids, principally a steroid hormone called cortisol. While rare in childhood, it carries the risk of adrenal crisis in the event of a child becoming unwell as a result of intercurrent illness, injury or surgery. Children’s nurses must be vigilant in caring for a child with adrenal insufficiency and have a clear understanding and awareness of the principles of emergency management at home and in hospital.

Keywords

adrenal crisis, child health, endocrine conditions, endocrine disease, endocrine disorders, endocrine system, parents, patient education, patient information

Aims

This module aims to promote a better awareness of the children’s nurse role in caring for a child with adrenal insufficiency.

Intended learning outcomes

After reading the module and completing the time out activities, you should be able to:

• Explain the role and functions of the adrenal gland as part of the endocrine system.
• Describe what the term adrenal insufficiency means and the differing presentations.
• Recognise the importance of prompt sick day management and describe the principles of early intervention.
• Identify the priorities of care for a child with adrenal insufficiency and describe the role of the children’s nurse in managing a child with this condition in hospital.

Introduction

Adrenal insufficiency is a rare endocrine condition defined as the inadequate production or action of glucocorticoids, in particular the steroid hormone cortisol. It can predispose a child to the risk of adrenal crisis in the event of illness, stress or injury (Moloney and Dowling 2012) resulting in possible electrolyte disturbances, hypoglycaemia and shock (Fischer et al 2000). More severe outcomes can include seizures, coma and death. An increased risk of morbidity and mortality is associated with childhood adrenal insufficiency (Shulman 2007), with mortality three times higher than that of the general population (Swerdlow et al 1998).

Children with adrenal insufficiency require cortisol replacement therapy, which is generally managed by parents and carers at home. However, a child with adrenal insufficiency may present to hospital for a variety of reasons including intercurrent illness, injury, surgery, clinical procedures and diagnostic testing. This highlights the need for all children’s nurses to understand the issues involved in providing safe nursing care.

Learning Points 

1. Adrenal insufficiency is a rare endocrine condition defined as the inadequate production or action of glucocorticoids, in particular the steroid hormone cortisol.
2. A child with adrenal insufficiency may present to hospital for a variety of reasons including intercurrent illness, injury, surgery, clinical procedures and diagnostic testing.

Anatomy and physiology

The adrenal glands have many functions contributing to homeostasis in the body. Central to understanding endocrinology is the principle of feedback mechanisms. The normal mechanism of the hypothalamic-pituitary-adrenal (HPA) axis is reliant on a self-regulating feedback system which maintains cortisol levels in the blood within an acceptable physiological range. When cortisol concentrations in the blood are low the hypothalamus secretes corticotropin releasing factor (CRF). CRF is released, stimulating the anterior pituitary to produce adrenocorticotropic hormone (ACTH) which, in turn, stimulates the adrenal cortex to release cortisol into circulation (Figure 1).

Figure 1. Hypothalmic-pituitary-adrenal axis

Cortisol secretion is pulsatile, which means it is released into the bloodstream in pulses and according to need, and also follows a circadian rhythm. This diurnal pattern usually peaks in the morning before awakening, declines during the day and is low at midnight, thereby matching the physiological challenges that will arise as human beings become active and meet stressors in their environment.

Anatomical position

Adrenal glands lie superior to the kidneys. The left is pyramidal shape and the right is crescent shaped (Laycock and Meeran 2013). The adrenal glands consist of two parts: the medulla (inner) and the cortex(outer). The adrenal medulla produces adrenaline (epinephrine) and noradrenaline (norepinephrine). Secretions of these hormones are regulated by the sympathetic nervous system and are involved in the body’s natural ‘fight or flight’ response (Brook and Dattani 2012).

The adrenal cortex comprises three zones, which are shown in Figure 2.

Figure 2. Anatomy of the adrenal glands

The glomerulosa secretes mineralocorticoids. These hormones are important in metabolic control, in particular aldosterone, which is stimulated by the renin-angiotensin system and regulates sodium retention and potassium loss in the body while influencing electrolyte balance, blood pressure and blood volume. Impaired aldosterone production will increase renal sodium loss and reduce circulating blood volume causing hypotension, tachycardia and salt craving.

The fasciculata produces glucocorticoids. These hormones influence metabolic control and the body’s adaptation to stress. Cortisol is a vital stress hormone involved in maintaining routine physiological functions such as carbohydrate metabolism, blood glucose levels and blood pressure. Production is increased in response to physiological ‘stressors’. Glucocorticoids are also involved in protein and fat mobilisation and have an anti-inflammatory effect.

The reticularis secretes adrenal androgens, which control mid-childhood growth and secondary sexual characteristics such as axillary and pubic hair. Overproduction of these androgens can lead to virilisation in females, for example, congenital adrenal hyperplasia. Most androgens are modulated by the testes in males post puberty (Brook and Dattani 2012).

In summary:

• Corticosteroids, which include mineralocorticoids (aldosterone) and glucocorticoids (cortisol), have significant physiological actions in maintaining homeostasis.
• Aldosterone is central to sodium retention and potassium excretion, a process regulated by the renin-angiotensin system.

The function and action of cortisol is complex and it has widespread influence on various processes including (Brook and Dattani 2012, Laycock and Meeran 2013, Hendry et al 2014):

• Carbohydrate metabolism to maintain blood glucose concentration.
• Renal effects including influence on normal water excretion.
• Cardiovascular effects related to maintaining blood pressure.
• Bone health and growth and development, for example, stimulates lung growth in utero and affects linear growth.
• Central nervous system processes.

It is important to understand the function of cortisol in the body’s response to internal and external stressors.

Learning Points 

1. Central to the understanding of endocrinology is the principle of feedback mechanisms.
2. Cortisol secretion is pulsatile and this diurnal pattern usually peaks in the morning before awakening, declines during the day and is low at midnight.
3. Parts of adrenal glands are the medulla (inner) and the cortex (outer).
4. Adrenal medulla (inner) produces adrenaline (epinephrine) and noradrenaline (norepinephrine).
5. Corticosteroids, which include mineralocorticoids (aldosterone) and glucocorticoids (cortisol), have significant physiological actions in maintaining homeostasis.
6. Aldosterone is central to sodium retention and potassium excretion, a process regulated by the renin-angiotensin system.

Aetiology of adrenal insufficiency

Paediatric adrenal insufficiency has a multi-faceted aetiology and can be classified as primary, secondary or tertiary (Quinkler et al2013). Figure 1 illustrates where on the hypothalamic-pituitary-adrenal axis (HPA axis) the classification of these three types of insufficiency occurs. Presentation can be congenital or acquired with acute or chronic clinical features (Hsieh and White 2011).

Primary disease results from adrenal gland dysfunction and children can have glucocorticoid and mineralocorticoid insufficiencies.

Secondary and tertiary adrenal insufficiencies occur as a result of dysfunction of either the hypothalamus (CRF insufficiency) or pituitary (ACTH insufficiency) and children only require glucocorticoid replacement therapy.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is the most common cause of childhood primary adrenal insufficiency with an approximate incidence of 1:18,000 live births (Khalid et al 2012). It is an autosomal recessively inherited condition causing inadequate production of cortisol and aldosterone and excess adrenal androgens. Specific enzymes are involved in synthesis of adrenal steroid hormones. The absence or deficiency of any of these at different points on the steroid pathway will result in differing clinical presentations. Categories of CAH include:

• Salt wasting.
• Simple virilising.
• Non-classical.

A deficiency in the enzyme 21-hydroxylase is the most common category of CAH (Box 1).

Box 1. Key terminology

Term	Explanation
21-hydroxylase deficiency	An enzyme deficiency in the synthesis of cortisol and aldosterone.
Salt wasting	Insufficient production of aldosterone and cortisol leading to loss of sodium.
Virilising	Masculinisation of external genitalia due to excessive androgen production in fetal development, about tenth week of gestation or can present later in childhood.

Male neonates typically present in the second week of life with hypoglycaemia, vomiting and poor feeding leading to acute hyponatremic crisis in salt-wasting CAH, whereas females present with ambiguous genitalia and are usually diagnosed at birth.

Virilisation is also exhibited in children with simple virilising CAH presenting in early childhood in addition to premature pubarche (early onset of pubic hair), tall stature and advanced bone age. Adolescent girls with non-classical CAH are usually asymptomatic but can present later in childhood with hirsutism (Speiser et al 2010).

Addison’s disease is commonly used to describe other causes of primary adrenal insufficiency including autoimmune adrenalitis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and adrenoleukodystrophy (ALD). Hypopituitarism, pituitary and hypothalamic tumours, such as craniopharyngiomas, and cranial radiotherapy are causes of secondary and tertiary adrenal insufficiency.

Prolonged high dose glucocorticoid therapy is the most common cause of tertiary disease (Charmandari et al 2014).

Adrenal crisis

Adrenal crisis can be the first presentation of chronic adrenal insufficiency in addition to a physiological stressor such as intercurrent illness, prolonged fasting or surgery. Acute adrenal crisis can occur if cortisol replacement medication is not administered correctly or there is failure to implement appropriate glucocorticoid sick day regimens. Adrenal crisis is life threatening and individual plans, referred to as sick day regimens, are put in place for children with adrenal insufficiency aimed at increasing cortisol levels to enable their bodies to cope with physiological stress during episodes of illness.

Acute and chronic adrenal insufficiencies share a number of clinical features (Box 2).

Box 2. Signs and symptoms of adrenal insufficiency

• Nausea.
• Vomiting.
• Fatigue/lethargy.
• Dizziness.
• Hypotension.
• Weight loss.
• Salt craving (primary adrenal insufficiency).
• Hyperpigmentation (seen in chronic Addison’s disease). This may be generalised (child may be sallow in appearance) or localised to areas such as knuckles, elbows and knees.
• Abdominal pain and pyrexia (occur in acute onset).

Adrenal insufficiency with pituitary or hypothalamic tumours

Signs and symptoms:

• Headaches and visual disturbances; peripheral vision is commonly affected.

Severe symptoms:

• Electrolyte imbalances (in particular hyponatremia, also hyperkalaemia in primary disease), hypoglycaemia, hypovolemic shock and collapse.

Emergency management should therefore include electrolyte and fluid replacement, correction of hypoglycaemia and immediate hydrocortisone administration on suspicion of diagnosis, either intravenously or intramuscularly, once blood sampling is obtained for cortisol and ACTH levels.

The case study below provides an example of the presentation and management of a child who has presented to the emergency department with signs and symptoms of adrenal insufficiency (Box 3).

Box 3. Case study

Megan is eight years old and attending the emergency department with a three-week history of worsening epigastric pain and frequent vomiting. A month earlier she had attended the GP with symptoms of lethargy and fatigue; routine bloods at this time were normal. Her parents felt she had lost ‘a lot of weight’ and had developed salt craving, for example, eating lots of processed ham and licking the inside of popcorn/crisp packets when empty.

On examination, Megan appeared lethargic, her skin appeared sallow (she had not been on holiday recently) and was showing signs of dehydration with sunken eyes, dry skin and mucous membranes. One possible diagnosis was Addison’s disease.

Baseline blood samples were taken. Her sodium level was low, at 112mmol/L (133-145mmol/L). She was hypoglycaemic, with serum glucose of 2.0mmol/L (3.3-5.0mmol/L). Blood gas analysis indicated acidosis. Blood samples were also taken for cortisol, ACTH, renin and adrenal antibodies. Cortisol level was low, at 56nmol/L (200-600nmol/L). An abdominal X-ray produced normal results.

Intravenous (IV) 0.9% saline and 10% glucose boluses were administered. IV hydrocortisone 100mg bolus also administered and Megan subsequently commenced on stress doses of hydrocortisone. IV maintenance fluids and an antiemetic were administered.

Sodium was corrected slowly over 72 hours with an IV saline infusion. Fludrocortisone was also commenced within 24 hours of admission.

Megan’s condition was stabilised and she was discharged home four days later. Sodium on discharge was 135mmol/L. The family received extensive teaching and information from the nurse specialist about sick day management at home. They also received an emergency medication pack before discharge and follow up in outpatients was arranged for one month. Contact details of the nurse specialist were provided. Wearing of a medic-alert bracelet was advised.

Outstanding ACTH and renin results were grossly elevated above normal physiological levels and adrenal antibodies were positive. A diagnosis of Addison’s disease was confirmed.

(End case study)

Complete time out activity 2

Read the case study outlined in Box 3. Considering the non-specificity of signs and symptoms, identify the elements of the parent’s history that would trigger specific concerns. Megan’s parents will need information to understand the sudden life-threatening condition of their daughter and the dramatic recovery. Progress your understanding by re-reading the previous section and applying the information to begin developing a rationale for Megan’s symptoms. These are complex processes and you will continue to enhance your understanding as you work through this module.

Learning Points

1. CAH is the most common cause of childhood primary adrenal insufficiency.
2. Primary disease results from adrenal gland dysfunction and children can have glucocorticoid and mineralocorticoid insufficiencies.
3. Hypopituitarism, pituitary and hypothalamic tumours, such as craniopharyngiomas, and cranial radiotherapy are causes of secondary and tertiary adrenal insufficiency.

Diagnostic testing

Classification of adrenal insufficiency relies on specific diagnostic testing. A low morning serum cortisol level is suggestive of adrenal insufficiency if a child presents with strong clinical indicators such as presenting symptoms and medical history. Pigmentation is seen in primary adrenal insufficiency because of increased ACTH levels; melanocyte-stimulating hormone (MSH) and ACTH share the same precursor pathway.

An ACTH stimulation test can be carried out to evaluate adrenocortical function. Tetracosactide is a synthetic form of ACTH used to assess the stimulated response of cortisol and is useful in the diagnosis of primary adrenal insufficiency and congenital adrenal hyperplasia. Caution must be undertaken in evaluating secondary disease as a subtle ACTH deficiency may be missed. The test is contraindicated in children with a known sensitivity to ACTH. Although rare, side effects include anaphylaxis. This test should be carried out by experienced staff with access to nearby resuscitation facilities and appropriate adrenaline autoinjectors.

A low, standard or high dose of tetracosactide may be given based on the child’s body surface area or age and suspected diagnosis, a physiological dose (usually one microgram) is considered more effective in detecting adrenal suppression from exogenous steroid therapy (Brook and Dattani 2012). The test involves intravenous (IV) cannula insertion, a baseline cortisol level before the administration of IV tetracosactide. Repeat serum cortisol levels are taken from the IV cannula at 30 and 60 minutes after medication administration. Dosing and timing of venous samples may vary between centres. A peak cortisol level ≥500nmol/L is accepted as a normal response (Grugni et al 2013, Charmandari et al 2014).

An ACTH level should be taken at the start of the test if Addison’s disease is suspected. A basal ACTH is increased and cortisol levels remain low in Addison’s disease. In secondary and tertiary insufficiency, ACTH and cortisol levels are supressed. Baseline and stimulated 17-hydroxyprogesterone (17-OHP) levels are also useful in the diagnosis of suspected simple virilising or non-classical CAH.

Insulin tolerance tests assess hypothalamic-pituitary-adrenal function. Insulin-induced hypoglycaemia stimulates the release of cortisol and growth hormone to counter-regulate the effects of hypoglycaemia.

This test is potentially hazardous and hypoglycaemic seizures have been described. It is generally performed in children aged more than four years and should be undertaken with caution. It is contraindicated in children with a history of seizures, blackouts and hypoglycaemia. Glucagon stimulation tests (GSTs) and prolonged fasts can also be used to test ACTH secretion in neonates and younger children. Specialist endocrine testing should only be conducted on a specialist unit with appropriate protocols and experienced staff (Raine et al 2011) and protocols, dosing and frequency of blood sampling may vary between centres.

Children with pituitary injury need vigilant and close monitoring as adrenal insufficiency can evolve subsequently up to six weeks after presentation (Hwang and Hwang 2014). It is also important to note that normal cortisol concentrations are required to diagnose antidiuretic hormone (ADH) deficiency resulting in diabetes insipidus (DI). Cortisol is necessary for the physiological excretion of free water from the body and a diagnosis of DI may be overlooked in a child who is cortisol deficient. Therefore, it is important to monitor fluid balance carefully and serum electrolytes when glucocorticoid therapy is introduced.

Diagnostic imaging such as magnetic resonance imaging of the brain is useful in assessing secondary and tertiary disease to visualise cranial anatomy and identify any anomalies. An autoantibody screen should be performed if a child has a second autoimmune disease such as hypothyroidism, hypoparathyroidism or diabetes mellitus given the link between Addison’s and APECED. Blood sampling for very long chain fatty acids should also be taken in boys presenting with Addison’s disease to investigate an underlying diagnosis of adrenoleukodystropy, an x-linked neurological disorder.

Complete time out activity 3

Can you identify and explain whether the following statements are true or false?

• Primary adrenal insufficiency occurs because there is damage to the adrenal gland.
• Secondary insufficiency results from dysfunction of the hypothalamus.
• Tertiary insufficiency occurs when the pituitary gland does not produce enough adrenocorticotropic hormone (ACTH).
• ACTH stimulation tests assess adrenocortical function.
• Insulin-tolerance tests can be undertaken to assess hypothalamic-pituitary-adrenal function.
• Administration of hydrocortisone may lead to a diagnosis of diabetes insipidus

Learning Points 

1. An ACTH stimulation test can be carried out to evaluate adrenocortical function.
2. Tetracosactide is a synthetic form of ACTH used to assess the stimulated response of cortisol and is useful in the diagnosis of primary adrenal insufficiency and congenital adrenal hyperplasia.
3. Children with pituitary injury need vigilant and close monitoring as adrenal insufficiency can evolve subsequently up to six weeks after presentation.
4. Cortisol is necessary for the physiological excretion of free water from the body and a diagnosis of DI may be overlooked in a child who is cortisol-deficient.
5. Diagnostic imaging such as magnetic resonance imaging of the brain is useful in assessing secondary and tertiary disease to visualise cranial anatomy and identify any anomalies.

1.