Addison's Disease

Introduction:

Addison’s, also known as primary adrenal insufficiency, was first described by Thomas Addison in 1855 as a syndrome of weakness and hyperpigmentation associated with adrenal gland destruction.
        

As a disease entity, Addison’s remains elusive due to its non-specific symptoms and the overall rarity of the disorder. In the western population the estimated prevalence of disease is approximately 90 to 140 cases per 1 million.     
            

Addison’s is caused by any of three categories of adrenal gland pathologies that result in the inability to produce adequate amounts of glucocorticoid, mineralocorticoid, and adrenal androgens despite an increased concentration of adrenocorticotropic hormone (ACTH).

Pathologic etiologies          

1. Adrenal destruction:
       
   Any pathologic process that results in the damage of the adrenal gland. This destruction may be secondary to autoimmune damage, infections, metabolic, infiltrative, or metastatic diseases, or pharmacologic effects.    
         

• Autoimmune destruction:
     
  The commonest form of Addison’s outside of infancy, and accounts for 15 percent of cases in children. It may occur as an isolated event or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2). When this disease occurs spontaneously, it is likely that other diseases are present or will develop.
  • APS Type 1 consists of the triad of acquired hypoparathyroidism, chronic mucocutaneous candidiasis, and Addison’s. It affects males and females equally and often manifests in infancy or early childhood. Addison’s occurs in approximately 80% of patients with APS type 1.
         
  • APS Type 2 is defined by Addison’s, autoimmune thyroid disease and/or immune-mediated diabetes mellitus. APS Type 2 has a strong female bias and though it may manifest at any age, it tends to have an adult onset, normally within the fourth decade of life.
        
• Infection:
     
  Historically, infection has been an important cause of adrenal failure.
  • Mycobacterium Tuberculosis is the leading cause of Addison’s worldwide; fortunately, with the improvement of TB therapy, the incidence of TB induced adrenal insufficiency has decreased. TB now accounts for approximately 20% of cases in the developed world.
       
  • Meningococcal septicemias can lead to bilateral adrenal hemorrhage, subsequently causing circulatory collapse (Waterhouse- Freidrichsen Syndrome)
        
  • Chronic fungal, CMV, and HIV infections can lead to adrenal infiltration and subsequent adrenal failure
        
• X-linked recessive disorders of metabolism of long-chained fatty acids (LCFA)
        
  These are characterized by progressive neurologic dysfunction and primary adrenal insufficiency.
  • Adrenoleukodystrophy and adrenomyeloneuropathy affect 1 in 20,000 males and account for up to 10% of all cases of adrenal insufficiency (AI) in children and men.
        
    Defective beta-oxidation in peroxisomes leads to accumulation of LCFA in the adrenal cortex. AI presents commonly in infancy with acute adrenal crisis, which often precedes the neurologic symptoms.
              
    Adrenoleukodystrophy begins in infancy or childhood with weakness and spasticity and progresses to dementia, blindness and quadriparesis. 
        
    Adrenomyeloneuropathy begins in adolescence or early adulthood with weakness, spasticity, and distal polyneuropathy. This disease is milder and progresses more slowly than adrenoleukodystrophy.

2. Adrenal dysgenesis:
       
   The development of the adrenal gland depends on multiple interacting genes. Mutations in any of the essential genes may lead to the presence of adrenal dysgenesis. In these conditions, adrenal androgen secretion is not increased and the response of cortisol and other precursors to ACTH stimulation is blunted or absent. Some examples include:

• DAX-1, a nuclear receptor protein causes an X-linked form of CAH, which presents in males with life threatening adrenal crisis in the newborn and hypogonadotropic hypergonadism later in adolescent.
     
• ACTH receptor gene mutation results in Familial Glucocorticoid Deficiency an autosomal recessive disorder in which cortisol and androgen secretion are deficient and unresponsive to ATCH stimulation.  It presents with hyperpigmentation, weakness, hypoglycemia, and seizures.

3. Impaired Steroidogenesis: 
             
   Disorders of cholesterol or steroid biosynthesis

• Cholesterol biosynthesis disorders:
  • Abetalipoproteinemia
  • Smith Lemli-Opitz syndrome
• Steroid biosynthesis disorders:
  • Congenital Adrenal Hyperplasia due to various enzyme deficiencies
    • 21-hydroxylase defiency is the most common cause of AI in early infancy and results from complete enzyme insufficiency, with defective production of both glucocorticoids and mineralocorticoids and severe salt wasting and adrenal crisis in the first 2-3 weeks of life
            
      Affected females have ambiguous virilized genitalia and are usually diagnosed at birth while males often are undiagnosed until they present with salt wasting
    • 3-beta-hydroxysteroid dehydrogenase deficiency can present with AI in the neonate with affected boys presenting with ambiguous genitalia or as phenotypically females.
  • Mitochondrial DNA mutations
    • May also cause AI and are characterized by chronic lactic acidosis, myopathy, cataracts, and nerve deafness
                   

Presentation    

It is important to consider the diagnosis of Addison’s with any of the following signs and symptoms, as it is commonly overlooked due the vagueness in its presentation. 

 Patients with chronic adrenal insufficiency usually complain of ill-defined fatigue, generalized muscular weakness, anorexia, weight loss, nausea & vomiting and recurrent abdominal pain.         

Patients may also experience salt craving, which can manifest itself in subtle ways. Patients may simply ask for foodstuff that contains salt, which can often be overlooked if the clinician is not actively searching for this behavior.

Patients may also experience signs of early depression, and muddy hyperpigmentation, which is a reflection of high concentrations of circulating corticotropin. The muddy hyperpigmentation, when present may be an indicator of longstanding adrenal disease. Areas unexposed to the sun often are hyperpigmented.   

Hyperpigmentation as seen in a woman with Addison's disease
https://en.wikipedia.org/wiki/Addison%27s_disease

Darkening of the gums due to increased pigment as seen in Addison's disease
https://en.wikipedia.org/wiki/Addison%27s_disease

Loss of pubic and axillary hair in adolescents may also be noted, as androgens support growth of body hair in these areas.
  

Patients with Addison’s Disease may present acutely in Addisonian crisis that involve sudden sharp leg pain, lower back or abdominal pain, nausea, vomiting, hyponatremic dehydration, hyperkalemia, metabolic acidosis, hypotension, hypoglycemia, shock or sudden death. This crisis occurs primarily with physiologic stress or when corticosteroid therapy is withdrawn without tapering the dose.

Differential Diagnosis

Additional differential diagnoses may include:

• Gastroenteritis
• Depression
• Iatrogenic glucocorticoid administration
• Infection: Tuberculosis, EBV, CMV, Histoplasmosis, HIV, Sepsis
• SIADH
• Type 1 Diabetes Mellitus
• Nutritional deficiencies
• Thyroid disease (Graves or Hashimotos)
• Eating disorder

A patient presenting with a salt-losing crisis with vomiting, hyponatremia, and hyperkalemia also can be seen in infants with obstructive uropathy, pyelonephritis, or tubulointerstitial nephritis. Hyponatremia and hyperkalemia may also result form chronic renal insufficiency.

Diagnosis         

Addison’s requires a high degree of suspicion and investigation. The basic laboratory workup should include the following:

• Vital signs: Including orthostatic BP, as some patients manifest postural hypotension
• Basic metabolic panel: Looking for hyponatremia, hyperkalemia, and hypoglycemia
• Basal early morning cortisol
• ACTH: Glucocorticoid deficiency is confirmed by an elevated plasma ACTH (>100 pg/mL) and low serum cortisol (<10 mcg/dL)
  • The short corticotropin stimulation test, which uses 250 μg of cosyntropin (α^1–24-corticotropin), is the most commonly used test for the diagnosis of primary adrenal insufficiency.
  • Stimulation test with ACTH should be performed if the diagnosis of Addison’s is in doubt. Normal response is a rise in serum cortisol concentration after 60 minutes to a peak of 18 mcg/dL
• Plasma renin: Mineralocorticoid deficiency is confirmed with a relatively low aldosterone level in the setting of hyperreninemia, with or without hyponatremia and/or hyperkalemia.
• If an enzyme defect in Steroidogenesis is suspected, ACTH levels along with an adrenal biochemical profile  (cortisol, aldosterone, androgen and precursors) may highlight the underlying enzyme defect.

Autoimmune workup

If the diagnosis of Addison’s appears to be a part of a larger autoimmune pathology, one should include a workup for other endocrine gland dysfunctions.

• Measuring serum calcium, phosphorus, glucose and thyrotropin
• Measure serum PTH if patient has hypocalcemia
• Hypogonadism should be investigated in post-menarchal female adolescents presenting in oligomenorrhea or amenorrhea by measuring FSH and LH. Possible hypogonadism in males should be investigated by measuring serum hypogonadism in males by measuring serum testosterone and LH.

Management

In patients with Addison’s disease, treatment includes physiologic replacement with glucocorticoid and mineralocorticoid.

Maintenance Therapy

Hydrocortisone is preferred in standard therapy because of its short duration of action and lower potency. Dosing is determined based on the estimates of normal cortisol secretion rates (7 to 12 mg/m²/day), pharmacokinetic and pharmacodynamic effects of parenteral hydrocortisone administration. Daily oral replacement dose of hydrocortisone is thus calculated to be 1.5 to 2 times that of the normal daily cortisol secretion rate, which is then divided into three doses and administered every eight hours.
     

Fludrocortisone is preferred for mineralocorticoid replacement. The daily dose is typically 0.1 mg, however, higher doses are occasionally needed in infants or in patients being treated with glucocorticoid that has minimal mineralocorticoid activity. Infants younger than 1 year may require sodium chloride supplementation of 1 gram (17 mEq) daily due to low dietary sodium intake. In older children, dietary intake of sodium is typically adequate without the need for further supplementation

Stress Conditions

Patients with primary adrenal insufficiency require additional doses of glucocorticoids when subjected to physiologic stress. The primary goal is to avoid adrenal crisis.
    

During conditions of moderate stress the dose of glucocorticoid should be doubled. In major stress (temperatures above 38 degrees C and/or vomiting), the hydrocortisone dose should be increase to three to four times the normal replacement.
     

Additionally children may not able to tolerate PO administrated of medications in stress conditionals. Parents are advised to administer medications IM injection of approximately 50 mg/m² of hydrocortisone or as follows:
     

• <3 years:                     25 mg
• 3 to 12 years:               50 mg
• 12 years and older:      100 mg

This treatment protocol will provide up to six hours of coverage, and allow the family time to get to medical attention.

Adrenal Crisis

Baseline labs should be drawn for electrolytes and glucose. If the patient does not have a diagnosis of adrenal insufficient additional labs must be drawn for measurement of serum cortisol and plasma ACTH prior to the administration of glucocorticoid therapy.
   

In terms of fluids and electrolytes, a fluid bolus of 5% dextrose with 0.9% saline without potassium, 20 mL/kg intravenously over one hour should be delivered. This will help to improve hyponatremic dehydration, and any possible hyperglycemia.  Life threatening hyperkalemia may require Kayexalate, IV calcium, insulin, and bicarbonate.
   

Treatment with a glucocorticoid, preferably hydrocortisone, should be given as soon as possible, delivered as an intravenous bolus over several minutes. Doses should be administered as follows:
    

• Infants and toddlers 0 to 3:            25 mg
• Children 3 to 12:                           50 mg
• Children and adolescents 12+:      100 mg

The initial bolus is followed by the same dose at a constant rate over 24 hours. Electrolyte and fluid balance must be monitored to prevent water retention. Once the crisis is treated a maintenance dose of glucocorticoid can be calculated and initiated.

Steps to improve medical management of Addison’s Disease for families

• Advise the use of a medical alert bracelet or necklace to be worn at all times stating the diagnosis of adrenal insufficiency and the need to administer hydrocortisone.
• Provide written instructions to the patient and family regarding how and when to increase glucocorticoid therapy. The instructions should be reviewed at each physician visit if not yearly so that the dose can be appropriately increased as the child grows.
• Instruct the family on the use of intramuscular hydrocortisone in case of vomiting, illness or severe stress
• Advise patients and their caretakers to seek medical consultation if the patient becomes ill.
• Provide information on support groups and other resources for assistance, sharing, and support. 
        
  CLICK BELOW for a listing of support groups from the National Adrenal Diseases Foundation:
                

References

1. Antal, Z., and Zhou, P. (2009). Addison disease. Pediatrics in Review, 30(12), 491-493. 
2. August, G.P. (1997). Consultation with the specialist: treatment of adrenocortical insufficiency. Pediatrics in Review, 18(2), 59-62. 
3. Bone, M., et. al. (2002). Assessment of adrenal function in the initial phase of meningococcal disease. Pediatrics, 110(3), 563-569.
4. Bornstein, S.R. (2009). Predisposing factors for adrenal insufficiency. NEJM, 360(22), 2328-2339.
5. Eisenbarth, G.S., and Gottlieb, P.A. (2004). Autoimmune polyendocrine syndromes. NEJM, 350(20), 2068-2079.
6. Rhen, T., and Cidlowski, J. A. (2005). Antiinflammatory actions of glucocorticoids - new mechanisms for old drugs. NEJM, 353(16), 1711-1723.
7. Shulman, D.I., et. al. (2007). Adrenal insufficiency: still a cause for morbidity and death in childhood. Pediatrics, 119(2), 484-494.