Adrenal Insufficiency

Introduction

Adrenal insufficiency is caused by failure of the adrenal glands to produce sufficient (or any) amounts of cortisol and aldosterone. Prolonged lack of cortisol leads to severe fatigue, chronic exhaustion, depression, loss of appetite and weight loss. Lack of aldosterone leads to a drop in blood pressure, particularly when standing up quickly, and to disturbed salt levels in the blood. Sometimes patients also describe a craving for salty food. Loss of DHEA (dehydroepiandrosterone) production by the adrenals results in loss of hair in pubic and underarm areas and also potentially reduced sex drive and low energy levels in women affected by adrenal insufficiency. A specific dark pigmentation of the skin is also sometimes observed, particularly in areas where the clothes rub against the skin and in areas exposed to increased friction, such as the creases of the hands.

There are three major types of adrenal insufficiency.

• Primary adrenal insufficiency is due to impairment of the adrenal glands.
  • 80% are due to an autoimmune disease called Addison’s disease or autoimmune adrenolytic.
  • One subtype is called idiopathic, meaning of unknown cause.
  • Other cases are due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland.
• Secondary adrenal insufficiency is caused by impairment of the pituitary gland or hypothalamus. Its principal causes include pituitary adenoma (which can suppress production of adrenocorticotropic hormone (ACTH) and lead to adrenal deficiency unless the endogenous hormones are replaced); and Sheehan’s syndrome, which is associated with impairment of only the pituitary gland.
• Tertiary adrenal insufficiency is due to hypothalamic disease and a decrease in the release of corticotropin releasing hormone (CRH). Causes can include brain tumors and sudden withdrawal from long-term exogenous steroid use (which is the most common cause overall).

Cortisol is important for life and its production by the adrenal glands is especially important at times when the body experiences intense ‘stress’, such as surgery, trauma or serious infection. If the adrenal glands cannot produce enough cortisol, the body might not be able to cope with this kind of major stress, which can be life-threatening. This situation is called adrenal crisis and is a medical emergency. Possible signs and symptoms of adrenal crisis are low blood pressure, abdominal pain, vomiting, nausea, severely abnormal salt levels in the blood that may affect the function of the heart and sometimes also fever and confusion.

Associated Anatomy

The adrenal glands sit at the top of the kidneys, one on each side of the body, and have an inner core (known as the medulla) surrounded by an outer shell (known as the cortex). The inner medulla produces adrenaline, the “fight or flight” stress hormone. While the absence of the adrenal medulla does not cause disease, the cortex is more critical. It produces the steroid hormones that are essential for life: cortisol and aldosterone. Cortisol mobilises nutrients, enables the body to fight inflammation, stimulates the liver to produce blood sugar and also helps control the amount of water in the body. Aldosterone regulates salt and water levels which affect blood volume and blood pressure. The adrenal cortex also produces sex hormones known as adrenal androgens; the most important of these is a hormone called DHEA.

Causes

Adrenal insufficiency arises if the adrenal glands are destroyed, absent or cannot function. Failure of the adrenal glands themselves is called primary adrenal insufficiency or Addison’s disease after Thomas Addison, who was the first to make the connection between disease of the adrenals and the clinical signs and symptoms described above. Addison’s disease is most often caused by autoimmune disease where the body’s immune system mounts an attack against its own adrenal cells. However, it can also be caused by infection, most importantly by tuberculosis.

Sometimes both adrenal glands are surgically removed for various reasons; this is called a bilateral adrenalectomy and is another cause of primary adrenal insufficiency.

There are also inborn causes of adrenal insufficiency which are caused by spelling errors in the genetic code. This includes the disruption of hormone production in the adrenals by different variants of congenital adrenal hyperplasia (CAH). In CAH, there is a spelling error in the gene responsible for the production of the protein that helps to generate cortisol in the adrenal; as a result cortisol and often also aldosterone levels are low. Another inborn cause of adrenal insufficiency is a condition called X-linked adrenoleukodystophy (ALD) or adrenomyeloneuropathy (AMN) that affects boys and men and can cause both adrenal insufficiency and neurological symptoms.

Another important cause of adrenal insufficiency is disease affecting the pituitary gland, an endocrine gland located behind the nose at the bottom of the brain. The pituitary is the master gland that tells all other glands in the body what to do. This includes not only the adrenals but also the thyroid and the gonads (testes or ovaries). The pituitary gland produces a hormone called ACTH (adrenocorticotropic hormone), which travels in the blood stream to the adrenal glands. Here it acts as a signal, causing the adrenal glands to produce more cortisol. ACTH is also responsible for the extra pigmentation found in primary Addison’s disease. Loss of the pituitary gland’s ability to produce ACTH is most often caused by a tumour in this area. If this happens and the pituitary gland stops making ACTH, this means that cortisol production by the adrenals is no longer controlled properly and a condition called secondary adrenal insufficiency arises. In this case, DHEA production usually declines as well. In most cases of secondary adrenal insufficiency, however, aldosterone is still produced, as its production is stimulated by other hormonal regulatory systems, involving the kidneys rather than the pituitary. This means that patients with secondary adrenal insufficiency usually have fewer problems with low blood pressure and disturbed salt levels in the blood. People with secondary adrenal failure also do not experience the extra pigmentation found in primary Addison’s disease.

Importantly, patients who receive treatment with synthetic steroid medications that have a similar action to cortisol, such as prednisone, prednisolone and dexamethasone, may also be at risk of developing adrenal insufficiency. This sometimes also applies to patients who receive steroids in the form of inhalers or by injection into a joint.

The presence of synthetic steroids in the blood leads the pituitary gland to ‘believe’ that enough cortisol is produced by the adrenals. The pituitary therefore decreases its production of ACTH and subsequently the adrenals also stop producing cortisol and go into a state of deep sleep, like a hibernation. This is not a problem as long as the tablets with the synthetic steroids continue to be taken at the correct dose. However, if they are suddenly stopped, life-threatening adrenal crisis could arise. Therefore, if synthetic steroids are no longer needed, (eg for the treatment of asthma or rheumatoid arthritis), their doses need to be gradually reduced over several weeks or months to ensure that the adrenal glands wake up again and start producing cortisol. These changes in medication should be only undertaken under close supervision of your doctor.

Differential Diagnosis

The differential diagnoses of neoplasia, acute appendicitis, cardiac dysrhythmias, subarachnoid hemorrhage, and acute coronary syndrome must be considered in patients with this disease. The nonspecific constellation of signs and symptoms, such as headache, visual changes, fatigue, generalized weakness, weight loss, abdominal pain, nausea and vomiting, syncope, and postural dizziness, often makes chronic adrenal insufficiency an elusive diagnosis for practitioners.

Drugs

Prednisone (Deltasone, Sterapred, Orasone)

Used for glucocorticoid hormone replacement. Longer acting than hydrocortisone, with a biologic half-life of 18-36 h.

Fludrocortisone (Florinef)

Synthetic adrenocortical steroid with very potent mineralocorticoid activity. For use in Addison disease and states of aldosterone deficiency.

Hydrocortisone sodium succinate or phosphate (Cortef, Hydrocortone)

Drug of choice for steroid replacement in acute adrenal crisis and for daily maintenance in patients with Addison disease or secondary adrenocortical insufficiency. Has both glucocorticoid and mineralocorticoid properties. Biologic half-life is 8-12 h. Easiest way to set up infusion is to have pharmacy mix 100 mg of hydrocortisone in 100 mL of 0.9 saline.

Epidemiology

In the United States, the prevalence of primary adrenal insufficiency (Addison disease) is 40 to 60 cases per 1 million population. Internationally, the occurrence is equally rare. The reported prevalence in countries where data are available is 39 cases per 1 million population in Great Britain, 60 cases per 1 million population in Denmark, and 144 cases per million in Norway. It is more common in women and diagnosis peaks during the fourth to sixth decades of life. In the United States, roughly 80% of cases are caused by autoimmune disorders.

The prevalence of secondary adrenal deficiency is estimated to be between 150-280/million. The most frequent occurrence is believed to be corticosteroid-induced insufficiency, despite the incidence of clinically relevant deficiency after cessation of glucocorticoid treatment being widely debated.

Acute adrenal deficiency (adrenal crisis) occurs in primary as well as secondary adrenal insufficiency. Its incidence, mostly determined in retrospective studies, is estimated in Europe at 6-8/100 patients/year. A prospective study reported 0.5 deaths/100 patient-years from adrenal crisis.

The autoimmune form of adrenal insufficiency and has male-female predisposition based on the type of autoimmune condition. Females are more likely to have the polyglandular form while isolated adrenal damage is more common in males in the first two decades. By the fourth decade, the isolated form is more common in women.

The epidemiology of adrenal insufficiency in children is not well-defined. Congenital adrenal hyperplasia (CAH) is the most common etiology of primary adrenal insufficiency in children, occurring once in 14,200 live births.

Natural Progression

Patients with adrenal insufficiency often present with hypotension, altered mental status, anorexia, vomiting, weight loss, fatigue, and recurrent abdominal pain. Reproductive complaints typically occur in women (amenorrhea, loss of libido, decreased axillary, and pubic hair). Salt craving and orthostatic hypotension are common in patients with primary adrenal insufficiency, due to the volume depletion from the reduced mineralocorticoid function. Obtaining a history of exogenous corticosteroid use is crucial in making the diagnosis, especially in cases of chronic adrenal insufficiency.

Patients may have poor skin turgor and increased skin pigmentation. Patients may also manifest neuropsychiatric signs and symptoms. One might notice signs of Cushing syndrome, such as skin atrophy, striae, edema, obesity, muscle wasting, and neuropsychiatric disturbance.

As many as half of the patients will develop shock with no preceding hypotension. Hypotension can be present in any form of adrenal insufficiency. Fever should lead to investigation for infectious etiology, although it can be present in any form of adrenal insufficiency.

Pathophysiology

The pathophysiology of adrenal insufficiency depends on the etiology. With most forms of autoimmune (primary) adrenal insufficiency, the patient has antibodies that attack various enzymes in the adrenal cortex (though cell-mediated mechanisms also contribute).

Secondary adrenal insufficiency refers to decreased adrenocorticotropic hormone (ACTH) stimulation of the adrenal cortex and therefore does not affect aldosterone levels. Traumatic brain injury (TBI) and panhypopituitarism are common causes.

Tertiary adrenal insufficiency refers to decreased hypothalamic stimulation of the pituitary to secrete ACTH. Exogenous steroid administration is the most common cause of tertiary adrenal insufficiency. Surgery to correct Cushing disease can also lead to tertiary adrenal insufficiency.

The other forms of adrenal insufficiency usually relate to destruction by infectious agents, or infiltration my metastatic malignant cells. Hemorrhagic infarction occurs due to sepsis with certain organisms (Neisseria species, tuberculosis, fungal infections, Streptococcus species, Staphylococcus species) or due to adrenal vein thrombosis. Death associated with adrenal insufficiency is usually of septic shock, hypotension, or cardiac arrhythmias.

Possible Complications

The predominant clinical features of adrenal crisis include hypotension and hypovolaemia (in patients with primary adrenal insufficiency (PAI) due to concomitant mineralocorticoid deficiency), but patients often have nonspecific symptoms, such as anorexia, nausea, vomiting, abdominal pain, fatigue, lethargy, fever or altered consciousness. The insidious onset of symptoms often results in a delay in diagnosis. Hypotension (particularly postural hypotension) occurs secondary to hypovolemia, but also due to hypocortisolism hence, if AI is not suspected, it may be refractory to parenteral fluids and inotropes. In PAI, hyponatraemia and hyperkalaemia can occur as a consequence of mineralocorticoid deficiency. The principal mechanism of hyponatraemia in SAI is reduction in the osmolar threshold stimulating vasopressin secretion secondary to hypocortisolism and the inability to excrete a free water load. The hyponatraemia that occurs in SAI is indistinguishable clinically from the syndrome of inappropriate antidiuresis (SIAD). In a prospective cohort of patients with SIAD, the incidence of SAI was 2.4%. Other biochemical features that can present in an adrenal crisis include renal impairment secondary to hypovolaemia, hypoglycaemia and, rarely, hypercalcaemia, which is due to decreased renal excretion of calcium and increased bone resorption.

Possible Treatment

In patients in acute adrenal crisis, IV access should be established urgently, and an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension. Some patients may require glucose supplementation. The precipitating cause should be sought and corrected where possible.

• In stress situations, the normal adrenal gland output of cortisol is approximately 250-300 mg in 24 hours. This amount of hydrocortisone in soluble form (hydrocortisone sodium succinate or phosphate) should be given, preferably by continuous infusion. 
  • Administer 100 mg of hydrocortisone in 100 cc of isotonic sodium chloride solution by continuous IV infusion at a rate of 10-12 cc/h. Infusion may be initiated with 100 mg of hydrocortisone as an IV bolus. Some hospitals mix 300-400 mg in 1 liter saline and infuse over 24 h to avoid needing to renew the infusion every 8-10 hours.
  • An alternative method of hydrocortisone administration is 100 mg as an IV bolus every 6-8 hours.
  • The infusion method maintains plasma cortisol levels more adequately at steady stress levels, especially in the small percentage of patients who are rapid metabolizers and who may have low plasma cortisol levels between the IV boluses.
• Clinical improvement, especially blood pressure response, should be evident within 4-6 hours of hydrocortisone infusion. Otherwise, the diagnosis of adrenal insufficiency would be questionable.
• After 2-3 days, the stress hydrocortisone dose should be reduced to 100-150 mg, infused over a 24-hour period, irrespective of the patient’s clinical status. This is to avoid stress gastrointestinal bleeding.
• As the patient improves and as the clinical situation allows, the hydrocortisone infusion can be gradually tapered over the next 4-5 days to daily replacement doses of approximately 3 mg/h (72-75 mg over 24 h) and eventually to daily oral replacement doses, when oral intake is possible.
• As long as the patient is receiving 100 mg or more of hydrocortisone in 24 hours, no mineralocorticoid replacement is necessary. The mineralocorticoid activity of hydrocortisone in this dosage is sufficient.
• Thereafter, as the hydrocortisone dose is weaned further, mineralocorticoid replacement should be instituted in doses equivalent to the daily adrenal gland aldosterone output of 0.05-0.20 mg every 24 hours. The usual mineralocorticoid used for this purpose is 9-alpha-fludrocortisone, usually in doses of 0.05-0.10 mg per day or every other day.
• Patients may need to be advised to increase salt intake in hot weather.

Surgical Care

Parenteral steroid coverage should be used in times of major stress, trauma, or surgery and during any major procedure.

During surgical procedures, 100 mg of hydrocortisone should be given, preferably by the IM route, prior to the start of a continuous IV infusion. The IM dose of hydrocortisone assures steroid coverage in case of problems with the IV access.

• When continuous IV infusion is not practical, an intermittent IV bolus injection every 6-8 hours may be used.
• After the procedure, the hydrocortisone may be rapidly tapered within 24-36 hours to the usual replacement doses, or as gradually as the clinical situation dictates.
• Mineralocorticoid replacement usually can be withheld until the patient resumes daily replacement steroids.

Consultations

Whenever possible, an endocrinologist should be involved in both the acute care and on-going treatment of these patients.

Primary Prevention

Many children are at risk for adrenal crisis. Pediatric nurses must be alert to patients presenting with the vague symptoms of adrenal insufficiency.

Assessing whether patients are taking glucocorticoids or have recently been on steroids is recommended.

Secondary Prevention

Once the diagnosis of adrenal insufficiency has been confirmed, clear and specific instructions must be provided to the family and patient. The following general guidelines are recommended for pediatric nurses who care for children with adrenal insufficiency.

1. Provide clearly written instructions to parents or caregivers at the time of the visit and review frequently.
2. Teach intramuscular injection of hydrocortisone in case of vomiting illness or inability to keep down oral medications and provide parents with the appropriate supplies to give injections.
3. Advise patients to wear medical alert identification that states, “Adrenal Insufficiency.”
4. Instruct parents to provide fluids containing sugar and salt (e.g., non-diet soda, juice, coke syrup, popsicles, sports drinks, soup) during times of illness.
5. Stress with parents that they should consult with a physician when a child with adrenal insufficiency becomes ill or requires surgery

Risk factors

Risk factors for adrenal insufficiency include:

• Genetic defects of adrenal gland
• Underactive parathyroid glands
• Pernicious anemia
• Chronic fungal infections
• Chronic active hepatitis
• Diabetes
• Vitiligo
• Tuberculosis
• Amyloidosis
• AIDS-associated infections
• Cancer
• Surgical removal of the pituitary gland or hypothalamus

Signs or Symptoms

Signs and symptoms include: hypoglycemia, dehydration, weight loss, and disorientation. Additional signs and symptoms include weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), cardiovascular collapse, muscle aches, nausea, vomiting, and diarrhea. These problems may develop gradually and insidiously. Addison’s disease can present with tanning of the skin that may be patchy or even all over the body. Characteristic sites of tanning are skin creases (e.g. of the hands) and the inside of the cheek (buccal mucosa). Goitre and vitiligo may also be present. Eosinophilia may also occur.

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Types

There are three major types of adrenal insufficiency.

• Primary adrenal insufficiencyis due to impairment of the adrenal glands.
  • 80% are due to an autoimmune disease called Addison’s disease or autoimmune adrenolytic.
  • One subtype is called idiopathic, meaning of unknown cause.
  • Other cases are due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland.
• Secondary adrenal insufficiencyis caused by impairment of the pituitary gland or hypothalamus. Its principal causes include pituitary adenoma (which can suppress production of adrenocorticotropic hormone (ACTH) and lead to adrenal deficiency unless the endogenous hormones are replaced); and Sheehan’s syndrome, which is associated with impairment of only the pituitary gland.
• Tertiary adrenal insufficiencyis due to hypothalamic disease and a decrease in the release of corticotropin releasing hormone (CRH). Causes can include brain tumors and sudden withdrawal from long-term exogenous steroid use (which is the most common cause overall).

Typical Test

Clinical Assessment

The onset of chronc Addison disease symptoms most often is insidious and nonspecific.

Hyperpigmentation of the skin and mucous membranes often precedes all other symptoms by months to years. It is caused by the stimulant effect of excess adrenocorticotrophic hormone (ACTH) on the melanocytes to produce melanin. The hyperpigmentation is caused by high levels of circulating ACTH that bind to the melanocortin 1 receptor on the surface of dermal melanocytes. Other melanocyte-stimulating hormones produced by the pituitary and other tissues include alpha-MSH (contained within the ACTH molecule), beta-MSH, and gamma-MSH. When stimulated, the melanocyte changes the color of pigment to a dark brown or black. Hyperpigmentation is usually generalized but most often prominent on the sun-exposed areas of the skin, extensor surfaces, knuckles, elbows, knees, and scars formed after the onset of disease. Scars formed before the onset of disease (before the ACTH is elevated) usually are not affected. Palmar creases, nail beds, mucous membranes of the oral cavity (especially the dentogingival margins and buccal areas), and the vaginal and perianal mucosa may be similarly affected. Hyperpigmentation, however, need not be present in every long-standing case and may not be present in cases of short duration.

Other skin findings include vitiligo, which most often is seen in association with hyperpigmentation in idiopathic autoimmune Addison disease. It is due to the autoimmune destruction of melanocytes.

Almost all patients complain of progressive weakness, fatigue, poor appetite, and weight loss.

Prominent gastrointestinal symptoms may include nausea, vomiting, and occasional diarrhea. Glucocorticoid-responsive steatorrhea has been reported.

Dizziness with orthostasis due to hypotension occasionally may lead to syncope. This is due to the combined effects of volume depletion, loss of the mineralocorticoid effect of aldosterone, and loss of the permissive effect of cortisol in enhancing the vasopressor effect of the catecholamines.

Myalgias and flaccid muscle paralysis may occur due to hyperkalemia.

Patients may have a history of using medications known to affect adrenocortical function or to increase cortisol metabolism.

Other reported symptoms include muscle and joint pains; a heightened sense of smell, taste, and hearing; and salt craving.

Patients with diabetes that previously was well-controlled may suddenly develop a marked decrease in insulin requirements and hypoglycemic episodes due to an increase in insulin sensitivity.

Impotence and decreased libido may occur in male patients, especially in those with compromised or borderline testicular function.

Female patients may have a history of amenorrhea due to the combined effect of weight loss and chronic ill health or secondary to premature autoimmune ovarian failure. Steroid-responsive hyperprolactinemia may contribute to the impairment of gonadal function and to the amenorrhea.

Presentation of acute Addison disease

Patients in acute adrenal crisis most often have prominent nausea, vomiting, and vascular collapse. They may be in shock and appear cyanotic and confused.

Abdominal symptoms may take on features of an acute abdomen.

Patients may have hyperpyrexia, with temperatures reaching 105° F or higher, and may be comatose.

In acute adrenal hemorrhage, the patient, usually in an acute care setting, deteriorates with sudden collapse, abdominal or flank pain, and nausea with or without hyperpyrexia.

Physical examination

Physical examination in long-standing cases most often reveals increased pigmentation of the skin and mucous membranes, with or without areas of vitiligo.

• Patients show evidence of dehydration, hypotension, and orthostasis.
• Female patients may show an absence of axillary and pubic hair and decreased body hair. This is due to loss of the adrenal androgens, a major source of androgens in women.
• Addison disease caused by another specific disease may be accompanied by clinical features of that disease.
• Calcification of the ear and costochondral junctions is described but is a rare physical finding.

Laboratory workup

Following tests can be performed for the diagnosis of adrenal insufficiency:

ACTH stimulation test: The ACTH stimulation test is the most common test for patients who are suspected of diagnosing adrenal insufficiency. During this test, before and after being injected ACTH, the patient is detected with the level of blood cortisol and urine cortisol. In normal person, after an ACTH injection, it may show a rise in blood and urine cortisol levels. Patients with causes of adrenal insufficiency have little or no increase in cortisol levels.

CRH stimulation test: This test can differ the primary and secondary adrenal insufficiency. In this test, the patient is injected synthetic CRH and measured blood cortisol before and 30, 60, 90, and 120 minutes after the injection. The leval of blood cortisol in people with primary adrenal insufficiency such as Addison’s disease, demonatrates high levels of ACTH but no cortisol. For the patients with secondary adrenal insufficiency, they appear absent or delayed ACTH.

Abdominal x-ray test: An x-ray image of abdomine allows the doctor to check the shape and size of the adrenal glands.

Abdominal ultrasound: This is an painless test which uses sound waves to create a picture of the internal organs. It can help doctor reveal any signs in adrenal glands.

Cranial CT and MRI: These imaging tests can confirm the size and shape of pituitary gland and hypothalamus and show the organs near them. It is useful for the diagnosis of secondary adrenal insufficiency. CT scan produce a series of x-ray pictures giving cross-sectional images. A magnetic resonance imaging (MRI) scan may show a three-dimensional image of this region.

 

References:

https://emedicine.medscape.com/article/116467-overview https://www.ncbi.nlm.nih.gov/books/NBK279122/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928659/
https://www.wikidoc.org/index.php/Adrenal_insufficiency_(patient_information)
https://www.uptodate.com/contents/clinical-manifestations-of-adrenal-insufficiency-in-adults#H2602056995
https://clinicaltrials.gov