Are You Confident of the Diagnosis?
Adrenocortical insufficiency (AI) is a condition of deficient adrenal production of glucocorticoids and/or mineralocorticoids.
Primary adrenal insufficiency, also called Addison’s disease (AD), is a result of destruction or dysfunction of the adrenal cortex, whereas in secondary AI the problem is in the pituitary gland (decreased adrenocorticotropic hormone secretion), and in tertiary AI the problem is at the level of the hypothalamus (decreased corticotropin-releasing hormone secretion). Both secondary and tertiary AI have the same clinical and laboratory findings.
Since aldosterone secretion is independent from the pituitary-hypothalamic axis, a finding of mineralocorticoid deficiency is a major distinction between primary and secondary AI. Mineralocorticoid deficiency is never seen in secondary or tertiary adrenal insufficiency, whereas it is almost always present in patients with AD.
Glucocorticoid deficiency causes generalized muscle weakness, chronic fatigue which typically improves with rest and worsens with activity, loss of appetite, anorexia, nausea, vomiting, diarrhea, depression, hypoglycemia, a craving for salty food, cold intolerance, and irregular or absent menstrual periods.
Mineralocorticoid deficiency produces electrolyte imbalance, dehydration and hypotension due to renal sodium wasting and potassium retention.
Acute adrenal insufficiency or Addisonian crisis is the initial presentation of AD in about 25% of newly diagnosed patients. A life threatening condition, it presents with sudden severe abdominal pain, vomiting, diarrhea, hypotension, fever and loss of consciousness. It may occur in a previously undiagnosed patient with primary adrenal insufficiency who has been subjected to major stress or after bilateral adrenal hemorrhage, or in a patient with known primary adrenal insufficiency who does not take additional glucocorticoid dose during a major illness.
Since the most common cause of AD in the Western world is an autoimmune adrenalitis, which is a fairly slow process, a great majority of patients will have insidious chronic symptoms and will ignore them for months until a stressful event causes them to worsen.
Characteristic findings on physical examination
The most characteristic finding on physical examination is hyperpigmentation (Figure 1), which occurs in almost all patients with AD (except in patients with acute onset of primary AI due to short duration of disease) and is never present in secondary or tertiary AI. It is one of the earliest signs of AD and usually starts in the buccal mucosa and gums and then affects the skin. It is most visible on scars, skin folds, lips, mucous membranes, and pressure points such as the elbows, knees, knuckles, and toes.
Darkening of the skin is caused by increased corticotrophin production by the pituitary gland in an attempt to stimulate the adrenal glands, which also stimulates melanin production. These features regress upon treatment with replacement corticosteroids.
Expected results of diagnostic studies
Common findings on routine biochemical and complete blood count profile are hyponatremia, hyperkalemia, uremia, eosinophilia and rarely hypercalcemia.
Once a clinical suspicion of Addison’s disease is raised, the diagnosis should be confirmed by assessing the hypothalamic-pituitary-adrenal axis to demonstrate inadequate cortisol production.
The first step is to check the basal cortisol secretion. In normal subjects serum cortisol levels peak around 6-8 AM with the normal range between 8 and 20mcg/dl. Although morning cortisol is not a reliable indicator of AI, based on current published data, AM cortisol levels less then 3 mcg/dl provide clear evidence that the patient has adrenal insufficiency while a value above 15mcg/dL virtually excludes the diagnosis. A salivary cortisol level is another screening method, but it is less commonly used and has different cutoff values.
In the second step, a Cosyntropin stimulation test is performed to assess adrenocortical reserve. The test can be performed at any time of the day and consists of intramuscular administration of 250mcg of synthetic human ACTH (Cosyntropin). Thirty to 60 minutes following Cosyntropin injection, serum cortisol level is measured again and a normal response is a peak serum cortisol level above 18-20mg/dl. A normal response to this stimulation test excludes the diagnosis of primary AI.
An inappropriately low response to a Cosyntropin test warrants the next step, in which plasma ACTH levels are checked to distinguish primary from secondary AI. In patients with primary adrenal insufficiency, plasma ACTH levels are always very high (normal plasma ACTH range is 10-60pg/ml and in patients with AD they usually exceed 100-200pg/ml), whereas in cases of secondary or tertiary AI, plasma ACTH levels are very low or low normal.
Baseline plasma ACTH levels should be checked before Cosyntropin injection on the following morning (to avoid false normal plasma ACTH results from synthetic ACTH used in Cosyntropin test) as well as prior to starting the steroid replacement dose (to avoid false low ACTH levels due to physiologic inhibition of ACTH by cortisol).
Checking plasma renin and aldosterone levels to asses mineralocorticoid deficiency is also frequently done in patients suspected for AI. Normal or high levels of aldosterone exclude primary AI, whereas high renin and low aldosterone levels are consistent with primary AI.
It is important to note that hydrocortisone and prednisone have cross-reactivity with the radioimmunoassay test of plasma cortisol and can give false normal or high cortisol levels. Therefore, patients who are already on those medications should be switched to an equivalent dose of dexamethasone for 24 hours prior to checking plasma cortisol levels or performing a stimulation test because dexamethasone does not cross-react with the radioimmunoassay of plasma cortisol.
The differential diagnosis of AD is very broad due to nonspecific initial symptoms and severity of acute crisis and it includes: hypothyroidism, congenital adrenal hyperplasia, pituitary tumor, depression, anorexia nervosa, chronic fatigue syndrome, anemia, acute abdomen, and septic shock.
Once the diagnosis of AD is established, further testing such as chest radiograph, abdominal CT, tuberculin testing, blood cultures and radioimmunoassay to detect adrenal autoantibodies are necessary to look for the etiology of AD. An abdominal CT scan may reveal small and atrophic cortical cells with preserved medulla in case of autoimmune AI and enlarged or calcified adrenals suggesting an infectious, hemorrhagic or malignant underlying causes of AI.
Who is at Risk for Developing Addison’s Disease?
The prevalence of AD is 35-140 per million populations with incidence of six cases per million adults per year.
It is usually diagnosed in adults in the third or fifth decades.
Patients with a history of other autoimmune endocrine disorders, malignancy, coagulopathy or AIDS are at increased risk for AD.
What is the Cause of Addison’s Disease?
Although all six out of 11 cases of primary AI that Thomas Addison described in 1855 were caused by hematogenous spread of tuberculosis, currently in the United States only 5% of patients with disseminated tuberculosis have significant primary AI.
Worldwide, infection is still the most common cause of AD, but in the western world, autoimmune adrenalitis accounts for more than 70% of all cases. Autoimmune adrenalitis can be sporadic or, in up to 50% of patients, can be part of an autoimmune polyendocrine syndrome, in which patients may also have hypofunction of the thyroid, parathyroid, gonads or pancreatic beta cells (type 1 diabetes mellitus), pernicious anemia, alopecia or vitiligo.
Patients with AIDS have significantly higher incidence of AD compared to the general population and approximately 10% will have an inappropriate response to a Cosyntropin test.
Fairly uncommon causes of AD include adrenal metastases (primary cancer being lung, breast, kidney or gastrointestinal) as well as necrosis of the adrenals due to intraadrenal hemorrhage which can occur in any severely sick patient, particularly those with underlying infection, trauma or coagulopathy.
Other causes such as congenital adrenal hypoplasia, Allgrove syndrome or adrenoleukodystrophies are rare genetic disorders and these patients present with signs and symptoms of AD in infancy or early childhood.
The etiology of primary AI can be categorized into three groups (Table I).
|l. Adrenal destruction||
Autoimmune adrenilitis – accounts for 70-80% of AD in adults in the Western world
Infections (tuberculosis, CMV, fungal, HIV)
Metastatic tumor- the most common primary being lung and breast
Infiltrations (amyloid, hemochromatosis)
Adrenoleukodystrophy (x-linked recessive disorder of defective beta-oxidation of very long chain fatty acids resulting in adrenal insufficiency and a progressive demyelination within the central nervous system)
ll. Adrenal dysgenesis
Congenital adrenal hypoplasia is due to mutation in gene superfamily such as DAX-1 or SF-1)
Familial glucocorticoid deficiency (FDG) – a rare autosomal recessive disorder in which cortisol and androgen secretion are deficient and unresponsive to ACTH stimulation
Allgrove’s syndrome (or triple A syndrome) is a form of FDG characterized by resistance to ACTH with subsequent cortisol deficiency in addition to achalasia and alacrima and frequently associated with progressive neurologic dysfunction, mental retardation.)
|III. Impaired steroidogenesis||
Congential adrenal hyperplasia – the most common cause of AI in children
Defects in cholesterol biochemistry including Wolman disease (accumulation of lysosomal esterified lipids due to lysosomal acid lipase deficiency resulting in calcification of adrenal glands, hepatosplenomegaly, malabsorption) and Smith-Lemli-Optiz syndrome (caused by mutation in the sterol 7-reductase gene, which catalyzes the final step in cholesterol biosynthesis leading to primary AI, mental retardation, microcephaly and ambiguous genitalia)
Mitochondrial disorders – characterized by chronic lactic acidosis, myopathy, cataracts, nerve deafness and often associated with AI, hypogonadism, diabetes, short stature, hypothyroidism, and hypoparathyroidism.
Primary AI is a result of destruction of the adrenal cortex, which consists of three layers producing three main types of hormone. The outer layer of the adrenal gland (zona glomerulosa, comprises approximately 15% of the cortex), produces mineralocorticoids, aldosterone. Cortisol is produced in zona fasciculata (comprises 75% of the adrenal cortex) and the most inner layer (zona reticularis, sharply demarcated from both the zona fasciculata and adrenal medulla) produces dehydroepiandrosterone (DHEA).
Clinical signs and symptoms of AI are not seen until 90% of the cortices are damaged, therefore, depending on the rate and extent of loss of adrenal function a patient can present to a medical provider with acute or chronic onset of symptoms.
In patients with chronic adrenal destruction, such as in autoimmune adrenalitis, the initial phase is decreased adrenal reserve, when the individual still has normal basal cortisol production, but insufficient levels for the stresses of surgery, trauma or infection. The next phase is further loss of cortisol production, leading to more obvious symptoms of AI. Mineralocorticoid deficiency usually occurs later on in the course of the disease. Due to decreasing levels of cortisol, plasma levels of ACTH increase, indicating insufficient adrenocortical reserve. Symptoms of androgen deficiency are less obvious and may present in women by reduced libido and decreased sexual hair.
Systemic Implications and Complications
Adrenal crisis is a medical emergency and if it is left untreated, it can lead to hypovolemic shock and death.
Chronic glucocorticoid deficiency leads to reduced sense of well-being, gastrointestinal symptoms (including nausea, vomiting and abdominal pain), and hypoglycemia, especially in children. Mineralocorticoid deficiency due to sodium wasting results in dehydration and hypotension.
Androgen deficiency is less obvious and might be present mostly in women by reduced libido and decreased sexual hair, since adrenal androgens represent a fairly insignificant contribution in males, because of the testicular production.
Treatment approach is different in patients who are presenting with Addisonian crisis versus long-term treatment of AD versus adjusting of glucocorticoids dose in patients with AD during minor or severe stress (Table II).
|Acute Addisonian crisis management||Maintenance therapy of AD||Therapy of AD during acute illness|
Draw blood for stat serum electrolytes, glucose and random plasma cortisol and ACTH, but do not wait for results to continue with treatment.
Correct volume depletion and hypoglycemia with 2 to 3 L of 0.9% saline or D5% in 0.9% NaCl as quickly as possible,than continue maintenance dose of fluids monitoring for signs of fluid overload (avoid hypotonic solutions, which can worsen hyponatremia).
Administer hydrocortisone 100mg intravenously every 6-8 hours until the patient is stable.
Hydrocortisone 15 to 30mg orally daily,divided in 2 or 3 doses (common regimen is15mg on awakening and 10 mg in the afternoon).
Instead of hydrocortisone, single dose of prednisone 5 – 7.5mg or or dexamethasone 0.25 – 0.75mg daily can be used.
Fludrocortisone maintenance daily dose is between 0.05 to 0.2mg orally.
For minor illness dose or mental stress, dose of glucocorticoid should be increased twofold to threefold for the few days of illness and than rapidly taper down to regular maintenance dose;.
For moderate to severe stress or trauma use hydrocortisone 50-100mg 2-4 x per day orally or intravenously. Taper rapidly to maintenance dose as patient recovers.
No need to change mineralocorticoid dose.
Optimal Therapeutic Approach for Addison’s Disease
AD has high morbidity and mortality if left untreated, but once recognized it is can be easily treated.
The goal of treatment of AI to administer enough dose of glucocorticoids and mineralocorticoids to mimic normal adrenocortical physiology and to avoid complications of side effects in overdosed patients.
Acute AI or Addisonian crisis is a life-threatening emergency manifesting as hypotension and acute circulatory failure. It appears more common in patients with septic shock, therefore clinicians should have a high index of suspicion for Addisonian crisis in critically ill patients with persistent hypotension despite adequate fluid resuscitation and poor hemodynamic response to vasopressors. Another important diagnostic clues like is the presence of hyponatremia, hyperkalemia and hypoglycemia.Other signs such as hyponatremia and hyperkalemia, should also help identify most cases.
When the Addisonian crisis is suspected, blood samples for the random cortisol and ACTH, in addition to plasma electrolytes and blood glucose, followed by treatment with hydrocortisone. Treatment should not be delayed while waiting for definitive proof of diagnosis. Cosyntropin stimulation test can be performed later on when patient is stable.
Patients should be given 1 to 2L of normal saline intravenously over the first hour and if hypoglycemia is present then 5% dextrose in normal saline should be added as maintenance fluid. Intravenous hydrocortisone should be given in a dose of 100mg immediately and then continue every 6-8 hours until patient is stable.
Once the patient is clinically stable, usually after the first 24 hours though improvement in the blood pressure should be seen within 4 to 6 hours in patients presenting with shock, the dose of hydrocortisone can be reduced, usually to 50mg every 6-8 hours. Then, if the patient can take oral medication, switch to a standard replacement dose of 20mg on wakening and 10mg around 5-6 PM.
Instead of hydrocortisone, use the equivalent oral maintenance dose of prednisone of 5 to 7.5mg or dexamethasone 0.5 to 0.75mg once.
It is very important to look for and adequately treat any precipitating cause of adrenal crisis, such as infection or ischemia.
Mineralocorticoid replacement therapy is not necessary as long as the patient is on normal saline and high dose of hydrocortisone. After the acute phase has passed, the adequacy of mineralocorticoid replacement should be assessed by measuring electrolytes and supine and erect blood pressure and plasma renin activity. Usual dose of fludrocortisones is 0.05 to .2mg daily.
Patients on glucocorticoid replacement therapy should be advised to double the daily dose in the event of febrile illness or any type of physical or mental stress. If the patient is vomiting and cannot take medication by mouth, parenteral hydrocortisone must be given urgently.
Based on recent evidence, use of dehydroepiandrosterone (DHEA) in primary AI is not recommended.
Monitoring blood pressure, edema, serum potassium, plasma renin activity and clinical signs of Cushing’s syndrome (from overtreatment with glucocorticoids) is essential.
Patients on glucocorticoid therapy as well as their families should receive regular education regarding the requirements of stress-related glucocorticoid dose adjustment and they should also wear a medical alert bracelet or necklace.
Unusual Clinical Scenarios to Consider in Patient Management
Pregnancy proceeds normally in patients with AD on replacement therapy, but doses of hydrocortisone are usually mildly increased in the last trimester. Due to a mineralocorticoid antagonist effect of progesterone during the pregnancy, it might be necessary to increased dose of fludrocortisone also.
Corticosteroids appear in breast milk and can suppress growth and interfere with infant endogenous corticosteroid production.
What is the Evidence?
Bornstein, SR. “Predisposing factors for adrenal insufficiency”. N Engl J Med. vol. 360. 2009. pp. 2328-39. (New insights into genetic disorders, infections, and medications that should be considered in the etiology of adrenal insufficiency and the current views on the underlying mechanisms of glucocorticoid insufficiency related to critical illness.)
Alkatib, AA, Cosma, M, Elamin, MB, Erickson, D, Swiglo, BA, Erwin, PJ. “A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency”. J Clin Endocrinol Metab. vol. 94. 2009. pp. 3676-81. (Meta-analysis of ten randomized controlled trials of DHEA effects in women with adrenal insufficiency showed minimal effect on depression, but no significant effect on anxiety or sexual well-being. Current evidence appears insufficient to support the routine use of DHEA in women with adrenal insufficiency.)
Arlt, W, Allolio, B. “Adrenal insufficiency”. Lancet . vol. 361. 2003. pp. 1881-93. (Overview article of epidemiology, etiology, pathophysiology, diagnoses and management of adrenal insufficiency.)
Dorin, RI, Qualis, CR, Crapo, LM. “Diagnosis of adrenal insufficiency”. Ann Intern Med. vol. 139. 2003. pp. 194-204. (Usefulness of the high- and low-dose cosyntropin stimulation test in the diagnosis of primary and secondary adrenal insufficiency.)
Ten, S, New, M, Maclaren, N. “Addison’s disease 2001”. J Clin Endocrinol Metab. vol. 86. 2001. pp. 2909-22. (Etiology, including new genetic insights, and diagnosis of Addison’s disease based on patient age and gender.)
Howlett, TA. “An assessment of optimal hydrocortisone replacement therapy”. Clin Endocrinol. vol. 46. 1997. pp. 263-8. (Retrospective study on 174 patients to assess optimal starting and maintenance replacement therapy with hydrocortisone.)
Oelkers, W. “Adrenal insufficiency”. N Engl J Med. vol. 335. 1996. pp. 1206-12. (A concise review of the diagnosis and treatment of primary and secondary adrenal insufficiency.)
Oelkers, W, Diederich, S, Bahr, V. “Diagnosis and therapy surveillance in Addison’s disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone”. J Clin Endocrinol Metab. vol. 75. 1992. pp. 259-64. (A review on plasma ACTH, renin , the ratios of ACTH/cortisol and renin/aldosterone, which are clearly elevated in 100% of the patients with Addison’s; plasma renin activity measurement is a valuable guide for fluodrocortisone replacement therapy.)
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- Are You Confident of the Diagnosis?
- Treatment Options
- Optimal Therapeutic Approach for Addison’s Disease
- Patient Management