A devastating but seldom diagnosis in itself, Addison’s disease in children requires customized, dedicated and often emergent management. This article envisages elaborating the basics about Addison’s disease in children and its management.
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Image: “EMT/Nursing Pediatric Emergency Simulation – April 2013 2” by COD Newsroom. Licence: CC BY-SA 2.0


Introduction

The adrenal glands secrete glucocorticoids, mineralocorticoids, and the androgen hormones. The hormonal output of the adrenal glands is essential for survival. Addison’s disease epitomizes a state of deficient adrenal hormones. Also known as adrenal insufficiency, it is a relatively infrequent clinical disorder.

History of Adrenal Insufficiency in Children

Addison’s disease is christened after Thomas Addison, a renowned British physician of the 18th century who discovered this disease and elaborated it extensively in “On the Constitutional and Local Effects of Disease of the Suprarenal Capsules (1855)”.

Epidemiology of Adrenal Insufficiency in Children

A seldom seen clinical condition in itself, adrenal insufficiency does not demonstrate gender or ethnicity based discrimination. Adults between 30—50 years are mainly afflicted.

Classification of Adrenal Insufficiency in Children

Adrenal insufficiency is classified as primary and secondary based on the pathological level of dysfunction.

A multitude of conditions can lead to primary adrenal insufficiency. The same can be summarized as follows:

  • Autoimmune adrenal insufficiency
  • Underdevelopment (transcription factor deficiencies) – rare
  • Impaired function (enzyme production problems) – rare
  • Smith-Lemli-Opitz syndrome
  • Destruction of adrenal gland (common)

Primary adrenal insufficiency is mostly the culmination of autoimmune processes, wherein the immune system attacks the adrenal glands. About 80 % of Addison’s disease patients are potentially the victims of such autoimmune destructive forces. Autoimmune primary adrenal insufficiency often occurs as a subset of a diverse congregation of autoimmune illnesses. The presence of one of these illnesses should prompt a meticulous search for the other.

The associated autoimmune conditions can be summarized as follows:

Adrenal destruction causing adrenal insufficiency is the result of a multitude of diverse etiologies such as mentioned below:

Etiology Explanation
Addison´s Disease Most common cause of acquired AI in children, usually, autoimmune destruction, may be part of PAS (polyglandular autoimmune syndrome)
Infection Meningococcal sepsis (Waterhouse-Friderichsen), tuberculosis
Metabolic Adrenoleucdystrophy (ALD) X-linked, males
Infiltrative Hemochromatosis, sarcoid, histiocytosis
Drugs Etomidate, Ketoconazole
Hemorrhage Birth trauma, sepsis, coagulopathy

Secondary adrenal insufficiency has an identifiable inciting factor which brings about the devastation of the adrenal cortex. The most significant relevant secondary causes of Addison’s disease can be summarized as follows:

  • Tumors
  • Fungal infections
  • Tuberculosis
  • Anticoagulants and blood thinners
  • HIV
  • Underdeveloped Hypothalamic-pituitary-adrenal axis
  • External glucocorticoid supplementation
  • Hypothalamic/pituitary destruction secondary to tumor or infarct circumstances

Etiopathogenesis of Adrenal Insufficiency in Children

Addison’s disease is primarily an adrenal insufficiency, which is a flaw in the adrenal production of Cortisol. Because the adrenal is affected broadly, mineralocorticoids are usually affected as well.

The spatially separate affection of the HPA-axis determines whether it is primary or secondary adrenal insufficiency.

HPA-Axis

  1. In primary adrenal insufficiency, the adrenals are damaged irrespective of the etiology. Consequently, there is a decline in production of Cortisol and mineralocorticoids. The adrenal hormones are essential for survival. The clinical manifestations emerge only when more than 90 % of the adrenal cortex is destroyed.

    Primary Adrenal Insufficiency

  2. In secondary disease, it is a pituitary or hypothalamic problem resulting in decreased stimulation of Cortisol. But mineralocorticoids production is stimulated by ACTH from another part of the pituitary, so it is still produced by the functioning adrenal gland.

    Secondary Adrenal Insufficiency

Clinical Presentation of Adrenal Insufficiency in Children

Addison’s disease is incompatible with survival. The most frequent presentation is of an insidious onset progressive crippling of the whole body. Early signs and symptoms are rather non-specific and hence often go unnoticed.

It is said that tan without tan lines is suggestive of high ACTH levels.

A brief summary of the clinical features is as follows:

Sign Symptom
Fatigue Weakness
Weight loss Lethargy
Generalized bronze discoloration of the skin Salt craving
Skin-fold hyperpigmentation Weight loss
Nausea Abdominal pain
Diarrhea Vomiting
Symptomatic Hypoglycemia Poor weight gain

The most prevalent features in the pediatric age group are lethargy and hyperpigmentation along with vomiting and peculiar salt craving. Some children remain undiagnosed due to the rather non-specific nature of the illness. They then have an unfortunate emergency presentation as they develop Addisonian crisis secondary to rather minor seemingly innocuous illness.

Few causes of Addison’s disease have unique presenting characteristics. The same can be tabulated as follows:

Etiology Presentation
Waterhouse–Friderichsen-Syndrome Mortality is very high. It is more common in children than adults.
Adrenoleukodystrophy It is very rare in girls and is characterized by an inability to break down long chain fatty acids. The buildup of fat damages myelin with resultant progressive weakness and ataxia. Adrenals are destroyed as well. Treatment is bone marrow transplant. Damage already done is done and hence the aim is to transplant early.

One needs to be aware of the phenomenon of Addisonian crisis when dealing with pediatric patients suffering from adrenal insufficiency.

Addisonian crisis

Also termed as the adrenal crisis or acute adrenal insufficiency, the Addisonian crisis is a potentially life threatening complication of Addison’s disease. The sudden drop in the level of glucocorticoids or relative acute deficiency of steroids in a patient with adrenal insufficiency secondary to either exposure to acute stress or interruption in intake of steroids leads to this crisis. Patients with congenital adrenal hyperplasia are also susceptible to this ill fate in times of intercurrent stressful circumstances.

One needs to be wary of the following clinical features of Addisonian crisis. The presence of a constellation of following symptoms calls for immediate attention and urgent treatment. They are as listed below:

  • Acute deep pain in back, legs or abdomen
  • Acute neurological deterioration in the form of confusion, convulsions, psychosis or slurred speech
  • Fever
  • Hypotension
  • Severe vomiting and diarrhea with consequent dehydration
  • Severe metabolic disturbances such as hypercalcemia, hyperkalemia, hypoglycemia, hyponatremia, and hypothyroidism
  • Syncope and severe lethargy

Diagnosis of Adrenal Insufficiency in Children

Addison’s disease is fundamentally diagnosed on the basis of simple blood tests such as Chem-7. The more complex tests are used to establish the etiology and document complications if any.

The various investigations involved and their changed behavior in light of Addison’s disease can be summarized as below for easy memorization and recall.

Test Change
Chem-7 All elements of Chem-7 are abnormal. The drift is as mentioned:

  • Sodium: Levels decrease
  • Chloride: Levels decrease
  • CO2: Levels decrease
  • Glucose: Levels decrease
  • Creatinine: Serum levels increase
  • Potassium: Serum levels increase
Serum ACTH High levels are documented in Primary adrenal insufficiency. Secondary adrenal insufficiency is characterized by low ACTH levels.
Serum Cortisol Adrenal insufficiency witnesses low Cortisol level irrespective of the etiology of adrenal insufficiency.
Other blood tests Blood serum level analysis of rennin and Aldosterone play an ancillary role in establishing the diagnosis.
Imaging studies There is no frank role of imaging investigations to confirm the diagnosis of Addison’s disease. However, they do play a significant role in documenting the complications if any. Tests thus useful are as follows:

Adrenal MRI is used to detect any hemorrhage or tumor.

MRI Brain comes in the picture in case of secondary adrenal insufficiency.

Management of Adrenal Insufficiency in Children

Addison’s disease is a medical diagnosis with a medical line of management. Treatment is steroids all lifelong. It specifically involves replacement of steroids either in the form of Hydrocortisone or Prednisolone in customized dosage form that suits the individual patient. A subset of patients also requires mineralocorticoids replacement in the form of Fludrocortisone.

Pediatric patients have to be wary of stressful circumstances which call for use of escalated doses of steroids to evade the occurrence of Addisonian crisis, a potentially life-threatening complication of Addison’s disease. Anything from dental treatment to a major surgery can induce stress in these patients. Infections are a significant relay for induction of crisis.

Hence, prompt medical attention and treatment of seemingly innocuous illnesses such as vomiting, diarrhea, and infections form an essential component of the management of Addison’s disease patients.

Treatment of Addisonian crisis

Specific treatment of Addisonian crisis demands emergent management as it is life threatening in nature. The key management steps are listed as follows:

  • Hydration with enormous stocks of intravenous saline solution with dextrose
  • Simultaneous intravenous steroids replacement, hydrocortisone used if oral replacement is appropriate
  • Occasional intramuscular saline injection if used if intravenous access is not available due to a myriad number of reasons
  • Oral fludrocortisone is used to replace mineralocorticoids if need be
  • Slowly treat hyponatremia over 1 to 2 days
  • Rapidly fix hypoglycemia and hyperkalemia

Special Issues of Adrenal Insufficiency in Children

Growth and puberty

Most of the pediatric patients are below average standard height percentiles when diagnosed. On receiving adequate optimum treatment, eventually, the linear growth is normal. Pubertal evolution is grossly uneventful in the majority of patients.

Summary

Addison’s disease, also known as adrenal insufficiency is incompatible with life. It is rare in the pediatric age group and is characterized by deficient levels of glucocorticoids circulating in the body. Mineralocorticoid production is occasionally hampered.

Primary adrenal insufficiency is most commonly secondary to autoimmune processes. The adrenal cortex is damaged.

Secondary adrenal insufficiency involves the infliction of the hypothalamus or pituitary due to disorders such as tumors, infections or infarcts which in turn disrupt the hypothalamic-pituitary- adrenal axis.

The HPA axis is indispensable to ensure proper steroid output to cope with different physiological and pathological challenges. Erratic control of the adrenals by the HPA axis in secondary adrenal insufficiency leads to adrenal insufficiency.

Clinical manifestations surface only when about 90% of the adrenal cortex is damaged. The first few signs and symptoms are rather nonspecific thus making early diagnosis a difficult task.

Addisonian crisis is acute adrenal insufficiency triggered by a multitude of potential stressors to the body.It is characterized by sudden acute neurological deterioration with a generalized systemic breakdown. It is potentially life threatening and requires emergency management with rapid administration of steroids and correction of the metabolic disturbances that follow.

Diagnosis of Addison’s disease rather follows a simple algorithm. Blood tests such as Chem-7 are useful for diagnosis. Determination of etiology and complications calls for more complex tests such as MRI adrenal and brain. The abnormalities in Chem-7 are:

  • Sodium, Chloride, CO2, and Glucose: Levels decrease
  • Creatinine and Potassium: Serum levels increase

Management involves steroid administration for life along with regular monitoring for metabolic disturbances. One should be always wary of Addisonian crisis.

Final linear growth and puberty are relatively normal in optimally treated pediatric patients with Addison’s disease.

Review Questions

The correct answers can be found below the references.

1. Which of the following statements is false?

  1. Addison’s disease is common in children.
  2. Pubertal evolution is grossly uneventful in the majority of patients.
  3. A subset of patients with Addison’s disease also requires mineralocorticoid replacement in the form of Fludrocortisone.
  4. Adrenal insufficiency witnesses low cortisol level irrespective of the etiology of adrenal insufficiency.

2. Which of the following statements is true?

  1. Patients with congenital adrenal hyperplasia are resistant to the Addisonian crisis in times of intercurrent stressful circumstances.
  2. Hyponatremia needs to be fixed rapidly to avoid the risk of pontine demyelinates.
  3. Addisonian crisis can be triggered by minor infections and dental treatment visits if proper prophylactic steroid dose is not administered before such events.
  4. Surgical management is the first line of treatment for Addison’s disease.

3. Which of the following statements is correct regarding Adrenoleukodystrophy?

  1. Treatment involves bone marrow transplant.
  2. Treatment is transsphenoidal surgery.
  3. Treatment is the administration of antibodies against Gamma receptors.
  4. It is more common in boys and spares the adrenals.
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