Addison's Disease - Phys Exam 2 PDF

Addison’s disease Disease summary ○ Addison disease, also known as chronic primary adrenocortical insufficiency (CPAI), is a potentially life threatening neuroendocrine or hormonal disorder and chronic metabolic condition caused by destruction or dysfunction...

Addison’s disease Disease summary ○ Addison disease, also known as chronic primary adrenocortical insufficiency (CPAI), is a potentially life threatening neuroendocrine or hormonal disorder and chronic metabolic condition caused by destruction or dysfunction of adrenal cortical tissue ○ Addison disease is characterized by diminished glucocorticoid (i.e, primary cortisol) and, less commonly mineralocorticoid (i.e., primary aldosterone) and adrenal androgen function ○ In 1855, Thomas Addison, an English physician, provided the first detailed clinical description of CPAI in a classic paper entitled On the Constitutional and Local Effects of Disease of the Supra-Renal Capsules. Before 1950, AD usually resulted from an infection of the adrenal glands. ○ The most common causative infection was tuberculosis (TB), which remains the leading cause of AD in developing countries today ○ In Addison’s time, up to 90% of all cases of CPAI were the result from TB ○ In developed countries, including the US, AD most commonly results today from non-specific destruction of the adrenal glands by cells of the immune system (i.e., autoimmune reaction) ○ Common alternative terms used to describe AD are hypocortisolism, adrenocortical hypofunction, and adrenal insufficiency ○ It is important to note that there is a wide variety of causes of adrenocortical insufficiency in which injury or surgery to the hypothalamus or pituitary gland or the use of certain medications results in low serum cortisol and aldosterone concentrations ○ These conditions, however, are collectively referred to not as AD or CPAI, but as secondary adrenocortical insufficiency SIgnificance ○ Morbidity and mortality usually are due to delay or failure in making the diagnosis or failure to being hormonal replacement therapy ○ Patients have limited ability to respond to stress ○ Acute addisonian crisis (aka acute adrenal crisis) is a serious complication of inadequately treated AD, represents a medical emergency, and is often triggered by significant stress imposed on the body (e.g., due to injury, infection or emotional turmoil) ○ If immediate medical care is not implemented, death may result. Addisonian crisis is characterized by low blood pressure (i.e., hypotension), low blood levels of glucose (hypoglycemia), and high blood concentrations of potassium (i.e., hyperkalemia), all of which may contribute to the patient’s demise ○ For the patient with AD, missing even a single day of therapy can be fatal  ○ With slow-onset AD, significant low-level, nonspecific but debilitating symptoms may occur ○ Virtually 100% of patients with AD complain of chronic, low grade fatigue ○ Such fatigue may be due to hypoglycemia, an absolute or relative epinephrine deficiency, suboptimal dosing of medication, electrolyte imbalance, or illnesses that often occur simultaneously with AD (e.g., hypothyroidism) ○ Absolute deficiency of epinephrine may occur when the medulla of the adrenal glands is also rendered dysfunctional ○ Relative deficiency of epinephrine may occur when a deficiency of cortisol impairs the ability of blood vessels to respond to epinephrine and blood pressure decreases Causes and risk factors ○ Insults to the adrenal glands that cause AD are multiple ○ Most cases of AD (80%) are caused by gradual destruction of the outer layer of the adrenal gland (adrenal cortex) by the body’s immune system ○ This subtype of AD is referred to as autoimmune AD, a condition in which the immune system produced antibodies that attack adrenal cortical tissues and slowly destroys them, while often sparing the inner medulla of the adrenals ○ Autoimmune destruction of the adrenal glands may be localized or in part of a multiorgan process ○ Localized autoimmune adrenal insufficiency involves destruction of only the adrenal cortex, with no other organ involvement ○ During the pre-antibiotic era, TB was the most common cause and still is a major cause of CPAI in areas of the world where TB is common ○ However, TB causes only approximately 10% of all cases of AD in developed countries today ○ Adrenoleukodystrophy is an X-linked recessive disorder in which very long-chain fatty acids are not adequately metabolized and accumulate in the adrenal cortex, testes, brain, and spinal cord ○ The disease usually presents in childhood but may develop at any age and accounts for approximately one third of all cases of AD in male children ○ Hypogonadism (i.e., small gonads resulting in ovarian or testicular failure) is common ○ Disease include mania, psychosis, and cognitive impairment ○ Neurologic deterioration may be mild or severe ○ CNS disease often mimics symptoms of MS and occurs years after onset of adrenal insufficiency ○ Sometimes, other glands and organs are affected when a patient has AD and patients develop multisystem autoimmune disease, such as in the polyglandular autoimmune disease (PGAD)  ○ PGAD is classified into two types, commonly referred to as types I and II. ○ PGAD I usually presents in early childhood with mucocutaneous candidiasis, hypoparathyroidism with hypocalcemia, and abnormal development of the teeth and nails. Addison disease usually develops by age 15 years. ○ A varied spectrum of complications may develop during adulthood, including: hypogonadism hypothyroidism pernicious anemia (i.e., an autoimmune disease of the stomach that causes gastritis, subnormal vitamin B12 absorption, and vitamin B12 deficiency) alopecia areata (i.e., localized hair loss) vitiligo (i.e., localized loss of skin pigment) hepatitis PGAD I is caused by an abnormality in T cell-mediated immunity and is inherited as an autosomal recessive trait. ○ PGAD II usually presents in adulthood with AD and without hypoparathyroidism. It is commonly associated with Hashimoto thyroiditis (one cause of hypothyroid disease), Graves disease (one cause of hyperthyroidism), vitiligo, type 1 diabetes mellitus, alopecia, or celiac sprue. Pathophysiology ○ The adrenal glands are located immediately above the kidneys and are composed of 2 distinct regions ○ The inner medulla produced a group of hormones known as catecholamines (e.g., epinephrine and norepinephrine) ○ The outer cortex is composed of three layers of cells that have distinctive functions ○ The zona glomerulosa, the outer layer of the adrenal cortex, produced hormones known as mineralocorticoids ○ Mineralocorticoids, specifically aldosterone, help maintain blood volume, blood pressure, and water and salt balance by directing the kidneys to retain sodium ions and water while excreting potassium and hydrogen ions ○ When aldosterone synthesis is impaired, as in possible in AD, the kidneys are unable to regulate salt and water balance, causing both blood volume and blood pressure to decrease ○ Aldosterone production is regulated primarily through stimulation of adrenocortical cells by the hormone angiotensin II and, to a lesser extent by adrenocorticotropic hormone (ACTH) secreted by pituitary gland ○ Glucocorticoids, specifically cortisol, are produced in the zona fasciculata and zona reticularis, the middle and innermost layers of the adrenal cortex ○ The zona reticularis also produced the adrenal androgen dehydroepiandrosterone (DHEA)  ○ When demand for cortisol increases, the hypothalamus sends out corticotropin-releasing hormone (CRH) to the pituitary gland, which responds by producing and secreting ACTH. ○ When adrenocortical cells receive the ACTH signal, they respond by producing cortisol. ○ When demand for cortisol has been met, cortisol signals the pituitary to stop secreting ACTH into the bloodstream. ○ This is commonly referred to as negative feedback. ○ Addison disease occurs when the adrenal glands do not produce enough cortisol, and in some cases, aldosterone and/or adrenal androgens (in females) ○ The onset of disease usually occurs when 90% of total adrenocortical tissue is rendered dysfunctional The HPA axis regulates the secretion of cortisol from the adrenal glands in response to stress ○ Corticotropin-releasing hormone (CRH) is the chemical messenger between the paraventricular nucleus within the hypothalamus and the anterior pituitary gland ○ Adrenocorticotropic hormone (ACTH) released by the pituitary gland travels in the bloodstream to the adrenal glands where it stimulates cortisol release. ○ Cortisol contributes to the body’s physiological response to stress ○ Addison disease specific antibodies are responsible for the autoimmune destruction of the adrenal cortex and are present in 50-70% of patients with autoimmune AD Three such antibodies have been isolated Antibodies to steroid 21-hydroxylase are the most common and specific to the adrenal cortex Antibodies to steroid 17-hydroxylase and cytochrome P-450 are not as specific and are also found in the gonads of patients with AD, causing hypogonadism. The detection of these antibodies in patients without symptomatic AD represents a significant risk to progression to adrenal insufficiency. Apparently, a genetic abnormality in immune surveillance mechanisms causes a deficiency of functional suppressor T lymphocytes, which keep the immune response in check This deficiency allows a proliferation of plasma cells that produce immunoglobulins against cells within the adrenal cortex. With destruction of the adrenal cortex, negative feedback of the hypothalamus and pituitary gland is inhibited. Both CRH and ACTH are secreted continuously ○ ACTH and melanocyte-stimulating hormone (MSH) are both components of the same progenitor hormone or prohormone—proopiomelanocortin.  ○ When ACTH is enzymatically cleaved from its prohormone, MSH is a byproduct ○ Clinical manifestations of AD result primarily from low serum levels of cortisol (i.e., hypocortisolism), aldosterone (hypoaldosteronism), and (in female patients) DHEA and high serum levels of ACTH and MSH. ○ Hypersecretion of melanocyte-stimulating hormone Proopiomelanocortin ○ Hyperpigmentation Unchecked secretion of releasing hormones Diagnosis: Clinical manifestations and laboratory tests: ○ The evaluation of patients with suspected AD is a two-step process: ○ 1) diagnosis of primary adrenocortical deficiency and ○ 2) identification of the specific cause of AD. In its early stages, AD is difficult to diagnose. ○ Diagnosis is based on the clinical presentation of the patient, medical history, physical examination, and selected laboratory tests. ○ Patients usually present with features of both glucocorticoid and mineralocorticoid deficiency. ○ Predominant symptoms vary depending on the duration of the disorder. ○ The onset most often is gradual over several months (two thirds of cases) and clinical manifestations are non-specific, consistent with a slowly destructive process of the adrenal glands (such as autoimmune-induced CPAI). ○ However, onset may also be rapid if adrenal destruction is sudden (e.g., due to an adrenal hemorrhage) or if a stressor (e.g., infection) or sudden discontinuation of hormonal replacement therapy causes rapid decompensation in a patient with chronic adrenal insufficiency. ○ In one third of patients, AD develops rapidly, with 25% of these individuals experiencing an addisonian crisis when they first see a health professional. ○ Hyperpigmentation of the skin and mucous membranes is considered a clinical hallmark of AD and is present in 90% of patients with CPAI. ○ Furthermore, hyperpigmentation often precedes all other clinical manifestations by months to years. ○ Hyperpigmentation usually is generalized and the skin appears bronzed or suntanned. ○ Knuckles, elbows, knees, scars formed after onset of the disease, palmar creases, nail beds, the posterior neck, mucous membranes of the oral cavity (especially dento-gingival margins), nipples, vaginal and perianal surfaces are darkened in varying degrees. ○ The skin in pressure areas, such as the belt and brassiere lines, also darkens significantly. ○ Low plasma cortisol (3 µg/dL) between 6–8 A.M., when baseline cortisol levels are normally highest each day, strongly suggests AD, especially if accompanied by simultaneous elevation of plasma ACTH concentration (usually 200 pg/mL).  ○ Definitive diagnosis of adrenocortical insufficiency rests on the assessment of the functional capacity of the adrenal cortex to synthesize cortisol. ○ This is accomplished primarily by use of the rapid ACTH stimulation test, the most specific test used today for diagnosing AD. Blood is first drawn in two separate tubes for baseline cortisol and aldosterone values. Then, synthetic ACTH (cosyntropin) in a dose of 0.25 mg is given intravenously. Within 15–30 minutes of ACTH treatment, a normal adrenal cortex releases two to five times its basal plasma cortisol output. At either 30 or 60 minutes after cosyntropin administration, two more blood samples are drawn—one for cortisol assay and one for aldosterone determination. Both serum cortisol and aldosterone levels increase significantly in response to ACTH in individuals with normal adrenal function. A normal rapid ACTH stimulation test result excludes AD. Two criteria must be satisfied for a definitive diagnosis of AD: ○ minimum increase of 7 µg/dL in the baseline serum cortisol value does not occur after cosyntropin administration ○ serum cortisol level does not increase to at least 20 µg/dL within 30–60 minutes after cosyntropin administration Although ACTH stimulation is not normally the major stimulus for aldosterone synthesis, it increases aldosterone production to peak levels within 30 minutes. A low baseline plasma aldosterone value 5 ng/dL that fails to increase by at least 4 ng/dL 20 minutes after cosyntropin administration indicates subnormal mineralocorticoid function of the adrenal cortex. Addison disease: ○ Elevated serum potassium concentration (60-65% of patients) ○ Low fasting blood glucose concentration ○ Increased serum thyroid stimulating hormone levels with low serum thyroxine concentration (in patients with associated hypothyroidism) ○ presence of serum adrenal autoantibodies (50–70% of patients) and thyroid autoantibodies (45% of patients) ○ serum DHEA 1000 ng/mL excludes a diagnosis of AD, but DHEA levels 1000 ng/mL are observed in 100% of patients ○ When AD is not clearly autoimmune, chest x-rays are obtained to provide evidence for TB, fungal infection, or cancer as possible causes. ○ Computed tomography (CT) or magnetic resonance imaging (MRI) can be used to reveal adrenal lesions.  ○ MRI is superior to CT in differentiating adrenal masses, but MRI cannot distinguish a tumor from a localized inflammatory process. ○ Imaging of the abdomen will reveal small, non-calcified adrenal glands when the cause is autoimmune. ○ The adrenals are enlarged in the majority of cases if AD is the result of cancer, TB, fungal infection, hemorrhage, sarcoidosis, or amyloidosis. ○ Calcification of the adrenals is often noted in cases of tuberculous AD (usually during the chronic phase of infection) and fungal infection. Serious complications and prognosis: ○ With proper control, long-term prognosis is good. ○ When treated with appropriate replacement doses of glucocorticoids and, if necessary, mineralocorticoids, patients with AD can expect to live fully active lives with a normal life expectancy. ○ The most serious acute complication complication of AD is addisonian crisis, which can occur in patients who abruptly stop taking their medication or who experience a stressful episode, such as infection or trauma, without appropriately higher doses of glucocorticoids. ○ In patients with AD, exposure to even a minor illness or stress can trigger nausea, vomiting, muscular weakness, hypotension, dehydration, loss of consciousness, and shock. ○ Acute adrenal crisis is occasionally fatal ○ Patients who take excessive doses of glucocorticoid replacement medicines can develop Cushing syndrome, which also imposes serious adverse effects (e.g., hypertension and osteoporosis). ○ Patients with adrenoleukodystrophy may suffer serious neurologic disease, and patients with AD from TB may develop a life-threatening systemic infection. ○ Since over-the-counter preparations have variable potencies, it is best to take pharmaceutical-grade DHEA that has been formulated by a pharmacist. ○ No restrictions on physical activity are required. ○ The patient’s diet should include at least 150 meq of sodium each day with sodium intake increased in the event of excessive sweating or diarrhea. ○ Treatment also must include correction of any underlying disorders (e.g., TB). ○ Patients are advised to wear a medical alert bracelet that reads: “Adrenal insufficiency—takes hydrocortisone.” ○ In patients who present with addisonian crisis, intravenous (IV) access should be immediately established and an infusion of isotonic sodium chloride solution should be instituted to replenish sodium and chloride ions, restore blood volume, and correct hypotension. ○ IV hydrocortisone is given and some patients may require glucose supplementation. ○ The precipitating cause of the acute episode is sought and corrected, when possible.