Adrenal insufficiency diagnosis and treatment
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This document discusses adrenal insufficiency (also known as Addison's disease), which can be primary, secondary, or tertiary. Primary adrenal insufficiency is caused by damage or disease of the adrenal glands and can result from autoimmune disease, infections, tumors, or hemorrhage. Secondary adrenal insufficiency is caused by interference with ACTH production in the pituitary gland, while tertiary is caused by interference with CRH production in the hypothalamus. Symptoms include fatigue, gastrointestinal issues, electrolyte imbalances, and hyperpigmentation. Diagnosis involves tests to evaluate cortisol levels and response to ACTH stimulation. Treatment consists of replacing glucocorticoids like hydroc
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Adrenal insufficiency diagnosis and treatment
- 1. Adrenal insufficiency Pratap Sagar Tiwari, MD, Lecturer Department of Internal Medicine
- 2. Adrenal Gland Pic taken from: uvahealth.com Pic taken from: www.gru.edu Pic taken from: http://en.wikivet.net/Adrenal_Glands_-_Anatomy_%26_Physiology A B C A.www.adrenalfatigue.co.nz B.www.gru.edu C.http://en.wikivet.net/Adrenal_Glands_-_Anatomy_%26_Physiology
- 3. Primary adrenal insufficiency (Addison's disease) Autoimmune adrenalitis Polyglandular autoimmune syndrome Infectious adrenalitis Tuberculosis Disseminated fungal infection HIV infection and AIDS Syphilis Metastatic cancer Primarily lung, breast, stomach and colon cancer or lymphoma Adrenal hemorrhage or infarction Drugs
- 4. Causes : Drugs Drugs Ketoconazole Fluconazole Rifampin Phenytoin Barbiturates Megestrol acetate Etomidate, metyrapone, mitotane
- 5. Secondary/tertiary Adrenal insufficiency • Hypothalamic /pituitary disease • Withdrawal of suppressive glucocorticoid therapy • Secondary AI can be caused by interference with corticotropin (ACTH) secretion by the pituitary gland. • Tertiary can be caused by interference with corticotropin-releasing hormone (CRH) secretion by the hypothalamus.
- 6. Clinical features Weakness, tiredness, fatigue Anorexia Gastrointestinal symptoms •Nausea, Vomiting, Constipation •Abdominal pain, Diarrhea Electrolyte disturbances Hyponatremia, Hyperkalemia, Hypercalcemia Anemia Weight loss Hyperpigmentation (1) Hypotension Vitiligo Salt craving Postural dizziness Muscle or joint pains
- 7. Approach to DIAGNOSIS 1. Demonstrating low cortisol secretion 2. Determining whether the cortisol deficiency is dependent on or independent of ACTH deficiency . 3. Seeking a treatable cause of the primary disorder (eg, histoplasmosis involving the adrenal glands or a pituitary adenoma compromising normal pituitary function)
- 8. • Serum cortisol concentration: An early morning low serum cortisol concentration (less than 3 mcg/dL [80 nmol/L]) is strongly suggestive of adrenal insufficiency. • Morning salivary cortisol concentration • Urinary cortisol measurements Note: Caution should be taken in interpreting the results in patients with abnormalities of cortisol binding globulin (CBG) or albumin, such as pts with cirrhosis or nephrotic syndrome, or those taking oral estrogens.
- 9. ACTH stimulation test S. Cortisol Plasma ACTH Low High primary adrenal insufficiency Low Low Secondary/tertiary Adrenal Insufficiency 250 μg ACTH1-24 (Synacthen) IM •Cortisol levels fail to ↑ in response to ex ACTH in pt with 1 or 2 AI. •Can be distinguished by mx of ACTH (which is ↓ in ACTH def & ↑ in AD. •If an ACTH assay is unavailable, then a long ACTH stimulation test (1 mg depot ACTH i.m. daily for 3 d); •In 2 AI :there is a progressive ↑ in plasma cortisol with repeated ACTH administration, •whereas in AD, cortisol remains <25.4 μg/Dl.
- 10. Adrenal Crisis The syndrome of adrenal crisis (acute adrenal insufficiency) in adults may occur in the following situations: 1.In a previously undiagnosed pt with primary AI who has been subjected to serious infection or major stress. 2.In a pt with known primary AI who does not take more glucocorticoid during an infection or other major illness. 3.After bilateral adrenal infarction or bilateral adrenal hemorrhage. 4.In patients who are abruptly withdrawn from doses of glucocorticoid that cause secondary AI.
- 11. Clinical and laboratory findings suggesting adrenal crisis • Dehydration, hypotension • Nausea and vomiting with a history of weight loss and anorexia • Abdominal pain, so-called "acute abdomen" • Unexplained hypoglycemia • Unexplained fever • Hyponatremia, hyperkalemia, hypercalcemia • Hyperpigmentation or vitiligo
- 12. Management of Adrenal Crisis Correct volume depletion I.v. saline Replace glucocorticoids I.v. hydrocortisone succinate 100 mg stat Continue parenteral hydrocortisone (50-100 mg i.m. 6-hourly) until the pt is well enough for reliable oral therapy Correct other metabolic abnormalities Acute hypoglycaemia: i.v. 10% glucose Identify and treat underlying cause Consider acute precipitant, e.g. infection Source: Davidson. 21st ed. THE ADRENAL GLANDS
- 13. Management of Adrenal insufficiency Replacement Glucocorticoid Hydrocortisone is the DOC. In someone who is not critically ill, hydrocortisone should be given by mouth, 15 mg on waking and 5 mg at around 1800 hrs. Mineralocorticoid Fludrocortisone 0.05-0.1 mg daily Androgen DHEA (approximately 50 mg/day) Source: Davidson. 21st ed. THE ADRENAL GLANDS
- 14. Thankyou • Davidsons • Uptodate 20.3 1. Lynnette K Nieman. Clinical manifestations of adrenal insufficiency in adults. 2. Lynnette K Nieman. Causes of primary adrenal insufficiency (Addison's disease). 3. Lynnette K Nieman. Diagnosis of adrenal insufficiency in adults 4. Lynnette K Nieman. Treatment of adrenal insufficiency in adults • Medscape 1. George T Griffing. Addison Disease 2. Elizabeth A Liotta. Dermatologic Aspects of Addison Disease
Editor's Notes
- The adrenal glands which r present at the top of the kidneys, one on each side of the body, also called suprarenal glands.It has 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. The several designated zones of cortex are glomerulosa, fasciculota and reticularis. We know the glomerulosa secrete mineralocorticoid,the major being the aldosterone that regulates salt and water levels which affect blood volume and blood pressure. Glucocorticoids secreted from fasciculota are the steroid ..the cortisol that is essential for life: . 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. The adrenal cortex also produces sex hormones known as adrenal androgens; the most important of these is a hormone called DHEA (dehydroepiandrosterone). Adrenal insufficiency results from inadequate secretion of cortisol and/or aldosterone. It is potentially fatal and notoriously variable in its presentation. A high index of suspicion is therefore required in patients with unexplained fatigue, hyponatraemia or hypotension. The most common is ACTH deficiency (secondary adrenocortical failure), usually because of inappropriate withdrawal of chronic glucocorticoid therapy or a pituitary tumour. Congenital adrenal hyperplasias and Addison&apos;s disease (primary adrenocortical failure) are rare.
- The transverse section of Adrenal gland shows outer cortex and the inner medulla. In the medulla of adrenal glands there are chromaffin cells . These chromaffin cells catecholamines: ~80% of Epinephrine (Adrenaline) and ~20% of Norepinephrine (Noradrenaline) into systemic circulation for systemic effects on multiple organs(.that is normal .) Chrommaffin cells are neuroendocrine cells that are in located in close proximity to pre-synaptic sympathetic ganglia of the sympathetic nervous system. So, the sympathetic division of the ans exerts direct control over the chromaffin cells ,the hormone release can occur rather quickly. In response to stressors such as exercise or imminent danger, medullary cells release catecholamines into the blood..so called fight or flight responses. The biologic effects of catecholamines are well known. Stimulation of alpha-adrenergic receptors results in elevated blood pressure, increased cardiac contractility, glycogenolysis, gluconeogenesis, and intestinal relaxation. Stimulation of beta-adrenergic receptors results in an increase in heart rate and contractility Note: pheochromocytoma secrete pheochromocytomas secrete norepinephrine predominantly, Catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla are referred to as &quot;pheochromocytomas”. The largest extra-adrenal cluster of chromaffin cells in is the organ of Zuckerkandl which is located at the bifurcation of the aorta or at the origin of the inferior mesenteric artery. It can be the source of paraganglioma or pheochromocytoma. --------------------------------------------------------------------------------------------------------------------------------------------------
- When Thomas Addison described the disease that now bears his name , bilateral adrenal destruction by tuberculosis was its most common cause. Now tuberculosis accounts for only 7 to 20 percent of cases; autoimmune disease is responsible for 70 to 90 percent, with the remainder being caused by other infectious diseases, replacement by metastatic cancer or lymphoma, adrenal hemorrhage or infarction, or drugs . Disseminated tuberculous or fungal infections are still a major cause of adrenal insufficiency in populations with a high prevalence of these diseases
- Metyrapone is a drug used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing&apos;s syndrome (hypercortisolism). Metyrapone blocks cortisol synthesis[by inhibiting steroid 11β-hydroxylase. This stimulates ACTH secretion, which in turn increases plasma 11-deoxycortisol levels. Etomidate suppresses corticosteroid synthesis in the adrenal cortex by reversibly inhibiting 11-beta-hydroxylase, an enzyme important in adrenal steroid production; it leads to primary adrenal suppression.
- Any process that involves the pituitary and interferes with ACTH secretion can cause secondary adrenal insufficiency. The ACTH deficiency may be isolated or occur in conjunction with other pituitary hormone deficiencies (panhypopituitarism). Secondary Adrenal insufficiency can be caused by interference with corticotropin (ACTH) secretion by the pituitary gland, and tertiary can be caused by interference with corticotropin-releasing hormone (CRH) secretion by the hypothalamus. Causes are: Hypothalamic /pituitary disease Withdrawal of suppressive glucocorticoid therapy Any causes leading to Panhypopituitarism, autoimmune disease, genetic defects..or traumatic brain injury. TERTIARY ADRENAL INSUFFICIENCY — The most common causes of tertiary adrenal insufficiency are: Abrupt cessation of high-dose glucocorticoid therapy Correction (cure) of hypercortisolism (Cushing&apos;s syndrome) Suppression of hypothalamic-pituitary-adrenal function by chronic administration of high doses of glucocorticoids is the most common cause of tertiary adrenal insufficiency. High doses of glucocorticoids decrease hypothalamic CRH synthesis and secretion. They also block the trophic and ACTH-secretagogue actions of CRH on the anterior pituitary. This results in decreased synthesis of POMC and decreased secretion of ACTH and other POMC-derived peptides by the pituitary corticotrophs. As a result, pituitary corticotrophs decrease in size, and eventually, the number of identifiable corticotrophs decreases . In the absence of ACTH stimulation, the zona fasciculata and zona reticularis of the adrenal atrophy and can no longer produce cortisol. Clinical features of secondary and tertiary adrenal insufficiency that help distinguish them from primary adrenal insufficiency include: Cortisol production can be restored by prolonged ACTH administration. Mineralocorticoid secretion is nearly normal because this function depends mostly on the renin-angiotensin system rather than on ACTH. The goal of tapering is to use a rate of change that will prevent both recurrent activity of the underlying disease and symptoms of cortisol deficiency due to persistent HPA suppression. We generally aim for a relatively stable decrement of 10 to 20 percent, while accommodating convenience and individual patient response. The dose is tapered by: 5 to 10 mg/day every one to two weeks from an initial dose above 40 mg of prednisone or equivalent per day. 5 mg/day every one to two weeks at prednisone doses between 40 and 20 mg/day. 2.5 mg/day every two to three weeks at prednisone doses between 20 and 10 mg/day. 1 mg/day every two to four weeks at prednisone doses between 10 and 5 mg/day. 0.5 mg/day every two to four weeks at prednisone doses from 5 mg/day down. This can be achieved by alternating daily doses, eg, 5 mg on day 1 and 4 mg on day 2.
- The clinical presentation of adrenal insufficiency is variable, depending on whether the onset is acute, leading to adrenal crisis, or chronic, with symptoms that are more insidious and vague. Therefore, the diagnosis of adrenal insufficiency depends upon a critical level of clinical suspicion. Adrenal crisis should be considered in any patient who presents with peripheral vascular collapse, whether or not the patient is known to have adrenal insufficiency. Likewise, isolated corticotropin (ACTH) deficiency, although rare, should be considered in any patient who has unexplained severe hypoglycemia or hyponatremia.
- Confirmation of the clinical diagnosis of adrenal insufficiency is a three-stage process Demonstrating inappropriately low cortisol secretion Determining whether the cortisol deficiency is dependent on or independent of ACTH deficiency and evaluating mineralocorticoid secretion in patients without ACTH deficiency Seeking a treatable cause of the primary disorder (eg, histoplasmosis involving the adrenal glands or a pituitary adenoma compromising normal pituitary function)
- In normal subjects, serum cortisol concentrations are higher in the early morning (about 6 AM), ranging from 10 to 20 mcg/dL (275 to 555 nmol/L), than at other times of the day. An early morning low serum cortisol concentration (less than 3 mcg/dL [80 nmol/L]) is strongly suggestive of adrenal insufficiency total serum cortisol as the diagnostic measurement. Caution should be taken in interpreting the results in patients with abnormalities of cortisol binding globulin (CBG) or albumin, such as patients with cirrhosis or nephrotic syndrome, or those taking oral estrogens. In these settings, decreased or increased levels may lead to an incorrect diagnosis. Salivary or serum free cortisol has been suggested as alternatives.
- If serum cortisol is inappropriately low and a simultaneous plasma ACTH concentration is very high, the patient has primary adrenal insufficiency (ie, primary adrenal disease). If both the serum cortisol and plasma ACTH concentrations are inappropriately low, the patient has secondary (ie, pituitary disease) or tertiary (hypothalamic disease) adrenal insufficiency. If the patient has hypopituitarism with deficient ACTH secretion and secondary adrenal insufficiency, then the intrinsically normal adrenal gland should respond to maximally stimulating concentrations of exogenous ACTH if given for a long enough time. The response may be less than in normal subjects and initially sluggish due to adrenal atrophy resulting from chronically low stimulation by endogenous ACTH. If, on the other hand, the patient has primary adrenal insufficiency, endogenous ACTH secretion is already elevated and there should be little or no adrenal response to exogenous ACTH. An inadequate serum cortisol response to ACTH stimulation establishes the diagnosis of adrenal insufficiency but does not distinguish between the primary and secondary forms Measurement of plasma ACTH in the basal sample. If it is higher than normal, the patient has primary adrenal insufficiency, whereas if it is low, the diagnosis is secondary or tertiary adrenal insufficiency. Measurement of the response of serum cortisol to prolonged ACTH stimulation. In primary adrenal insufficiency, prolonged stimulation results in little, if any, increase in cortisol production. In secondary adrenal insufficiency, on the other hand, the adrenal gland is intrinsically normal but is atrophic because of chronic ACTH deficiency.
- The predominant manifestation of adrenal crisis is shock, but the patients often have nonspecific symptoms such as anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, fever, confusion or coma . Hypoglycemia is a rare presenting manifestation of acute adrenal insufficiency; it is more common in secondary adrenal insufficiency caused by isolated corticotropin (ACTH) deficiency . Patients with long-standing adrenal insufficiency who present in crisis may be hyperpigmented (due to chronic ACTH hypersecretion) and have weight loss, serum electrolyte abnormalities, and other manifestations of chronic adrenal insufficiency . The major hormonal factor precipitating adrenal crisis is mineralocorticoid, not glucocorticoid, deficiency, and the major clinical problem is hypotension. Furthermore, patients with secondary adrenal insufficiency, in whom aldosterone secretion is usually normal, rarely present in adrenal crisis. Although it is not primarily responsible, glucocorticoid deficiency can contribute to hypotension by causing decreased vascular responsiveness to angiotensin II and norepinephrine, decreased synthesis of renin substrate, and increased prostacyclin production