Question 1 of 10

    Adrenal Insufficiency (Adrenal Failure)

    Illu adrenal gland[1]

    Adrenal insufficiency refers to an endocrine disorder resulting from a reduced production or the decreased action of hormones by the adrenal gland, mainly the steroid hormones. Symptoms primarily result from lack of mineralocorticoids and/or glucocorticoids and this condition may be triggered by lesions of the adrenal glands themselves or by pathologies of superior regulatory centers.

    Presentation

    Patients may present with rather non-specific symptoms or be admitted for emergency care because of an adrenal crisis. With regards to the former, symptoms develop gradually and comprise fatigue, lethargy, generalized weakness, gastrointestinal complaints, loss of appetite and weight, and hypotension. Depending on its severity, the latter may manifest in form of orthostatic hypotension or prolonged dizziness and syncopes. Patients may experience mood swings and behavioral disorders. Hyperpigmentation is common in patients suffering from primary AI, is of great diagnostic value, and is primarily noted in sun-exposed areas. Additional symptoms may result from mineralocorticoid deficiency - affected individuals frequently report to crave salt - and lack of androgens in females, which may cause delayed pubarche and reduced libido. Secondary AI may be accompanied by other endocrine disorders resulting from panhypopituitarism or more extensive lesions of the hypothalamus.

    The adrenal or Addisonian crisis is a life-threatening condition most commonly observed in individuals affected by primary AI. Patients may present with severe hypotension leading to reduced levels of consciousness and shock, with acute-onset high fever, nausea, vomiting and abdominal pain. Myalgia and arthralgia may also be experienced.

    Entire body system
    Collapse
    • Symptoms Adrenal insufficiency can present either as an acute crisis with vascular collapse or as a chronic insufficiency, which has much more obscure symptomology.[endocrinologyadvisor.com]
    • 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.[en.wikipedia.org]
    • As cortisol levels remain low, patients may develop severe hypotension, vascular collapse, acute renal failure, and hypothermia.[pharmacytimes.com]
    • On April 1 st , 2011, I nearly collapsed after walking up the stairs in my house.[livinglovingpaleo.com]
    • Sudden onset of insufficiency, such as the Waterhouse-Friderichsen syndrome (infarction secondary to septicaemia - eg, meningococcal) presents with collapse and shock.[patient.info]
    Fatigue
    • Fast facts on adrenal fatigue Here are some key points about adrenal fatigue .[medicalnewstoday.com]
    • Adopting the adrenal fatigue diet, adrenal fatigue natural supplements, and adrenal fatigue lifestyle including positive thoughts can help heal your adrenal glands.[drlam.com]
    • Patients are told that their fatigue is due to depression or stress.[onlinemedinfo.com]
    • Symptoms include dizziness, nausea and vomiting, and extreme fatigue, which usually follows a stress on the body such as dehydration, infection, or another illness or injury.[uclahealth.org]
    • Poor memory and fatigue 2.[ebnutrition.com]
    Weakness
    • Complications such as protracted weakness, shock, or death may result.[healthcommunities.com]
    • Depends on the course of the disease: acute stage: the patient presents with fever, back pain, hypotension, weakness chronic stage : progressive lethargy, weakness, cutaneous pigmentation, weight loss Laboratory data chemistry: hyponatremia, hyperkalemia[radiopaedia.org]
    • Symptoms include Weight loss Muscle weakness Fatigue that gets worse over time Low blood pressure Patchy or dark skin Lab tests can confirm that you have Addison disease.[fpnotebook.com]
    • While this condition may not have particular symptoms, hyperkalemia causes nausea, and irregular heartbeat – including slow, weak or irregular pulse.[drlam.com]
    Weight Loss
    • Symptoms include Weight loss Muscle weakness Fatigue that gets worse over time Low blood pressure Patchy or dark skin Lab tests can confirm that you have Addison disease.[fpnotebook.com]
    • Unexplained weight loss, anorexia, weakness, nausea, abdominal pain, arthralgias, fatigue, and malaise should be observed in most patients with adrenal insufficiency.[ime.acponline.org]
    • When to Call a Doctor See a doctor for any persistent unexplained weakness, weight loss, or stomach upset.[healthcommunities.com]
    • Symptoms Addison's disease symptoms usually develop slowly, often over several months, and may include: Extreme fatigue Weight loss and decreased appetite Darkening of your skin (hyperpigmentation) Low blood pressure, even fainting Salt craving Low blood[mayoclinic.org]
    • Signs and symptoms include: hypoglycemia, dehydration, weight loss, and disorientation.[en.wikipedia.org]
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  • neurologic
    Vertigo
    • Other symptoms include vertigo, hypotension, depression, salt craving, and vitiligo (depigmented patches of skin).[pharmacytimes.com]
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  • Skin
    Hyperpigmentation
    • hyperpigmentation does not occur.[medbullets.com]
    • Symptoms Addison's disease symptoms usually develop slowly, often over several months, and may include: Extreme fatigue Weight loss and decreased appetite Darkening of your skin (hyperpigmentation) Low blood pressure, even fainting Salt craving Low blood[mayoclinic.org]
    • Unlike in Addison disease, hyperpigmentation does not occur and serum sodium and potassium levels are relatively normal.[merckmanuals.com]
    • Clinical symptoms include ANOREXIA; NAUSEA; WEIGHT LOSS; MUSCLE WEAKNESS; and HYPERPIGMENTATION of the SKIN due to increase in circulating levels of ACTH precursor hormone which stimulates MELANOCYTES.[fpnotebook.com]
    • Hyperpigmentation often is seen in patients with Addison's disease because ACTH can stimulate melanocytes to produce excessive levels of melatonin.[pharmacytimes.com]
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  • gastrointestinal
    Diarrhea
    • Immediate medical attention is needed when severe infections, vomiting, or diarrhea occurs, as these conditions can precipitate an Addisonian crisis.[healthcentral.com]
    • In acute adrenal failure (addisonian crisis), the signs and symptoms may also include: Pain in your lower back, abdomen or legs Severe vomiting and diarrhea, leading to dehydration Low blood pressure Loss of consciousness High potassium (hyperkalemia)[mayoclinic.org]
    • Common symptoms of adrenal insufficiency include fatigue, weight loss, decreased appetite, muscle weakness, muscle and joint pain, nausea, vomiting, diarrhea, low blood pressure, low blood glucose and darkened skin.[themighty.com]
    • In worst case scenarios, adrenal insufficiency can become a life-threatening adrenal crisis with symptoms including: Sudden, intense pain in the lower back, legs or abdomen Severe diarrhea or vomiting Dehydration Loss of consciousness.[medicalnewstoday.com]
    • Call your healthcare provider if: You have any kind of illness, especially a fever, vomiting, or diarrhea You become pregnant You need surgery Get medical help right away if you have sudden severe symptoms (Addisonian crisis).[hopkinsmedicine.org]
    Nausea
    • Symptoms include dizziness, nausea and vomiting, and extreme fatigue, which usually follows a stress on the body such as dehydration, infection, or another illness or injury.[uclahealth.org]
    • Fatigue and nausea usually begin to disappear within days of starting treatment.[uptodate.com]
    • EMERGENCY If you have been diagnosed with Addison’s disease and experience symptoms of severe lethargy, nausea, vomiting, dizziness, or dehydration, get immediate medical assistance.[healthcommunities.com]
    • […] symptoms usually develop slowly, often over several months, and may include: Extreme fatigue Weight loss and decreased appetite Darkening of your skin (hyperpigmentation) Low blood pressure, even fainting Salt craving Low blood sugar (hypoglycemia) Nausea[mayoclinic.org]
    • Table 2 Variables associated with adrenal insufficiency Restricted model Glucocorticoid withdrawal 6.66 [2.94 ; 15.09] Nausea 3.48 [1.09 ; 11.14] 0.036 Broad model Glucocorticoid withdrawal 7.38 [3.18 ; 17.11] Nausea 3.37 [1.03 ; 11.00] 0.044 Eosinophilia[bmcendocrdisord.biomedcentral.com]
    Vomiting
    • In acute adrenal failure (addisonian crisis), the signs and symptoms may also include: Pain in your lower back, abdomen or legs Severe vomiting and diarrhea, leading to dehydration Low blood pressure Loss of consciousness High potassium (hyperkalemia)[mayoclinic.org]
    • A patient who is vomiting may require injections of hydrocortisone, since oral hydrocortisone supplements cannot be adequately metabolized.[healthcentral.com]
    • Symptoms include dizziness, nausea and vomiting, and extreme fatigue, which usually follows a stress on the body such as dehydration, infection, or another illness or injury.[uclahealth.org]
    • Signs include severe dehydration; pale, cold, clammy skin; rapid, shallow breathing; extreme sleepiness; severe vomiting and diarrhoea.[home.bt.com]
    • Adrenal crisis usually starts with vomiting and may quickly progress to a severe illness associated with abnormally low blood pressure, low blood sugar, a salt/water imbalance, lethargy and shock.[chop.edu]
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  • musculoskeletal
    Myalgia
    • […] illness, surgery, failure to take medications GI: abdominal pain, vomiting and diarrhoea CVS: dehydration, hypotension, refractory shock, poor response to inotropes/pressors fever confusion CHRONIC ADRENAL INSUFFICIENCY GENERAL: weight loss, arthalgia, myalgia[lifeinthefastlane.com]
    • Symptoms: Symptoms may include: Weakness Lethargy, fatigue Nausea and vomiting Arthralgias, myalgias (muscle pains) Low blood pressure (hypotension) that may cause light-headedness or fainting when the affected person stands after sitting or lying down[uclahealth.org]
    • Early signs of this medical emergency include malaise, weakness, and myalgias.[pharmacytimes.com]
    • Other symptoms may include weight loss, anorexia , myalgia, dizziness, fainting.[almostadoctor.co.uk]
    • The clinical presentation of AI may be subtle in the absence of an adrenal crisis, with the gradual development of nonspecific symptoms such as fatigue, weakness, diffuse myalgia, weight loss, nausea, anorexia [ 25 ].[omicsonline.org]
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  • cardiovascular
    Orthostatic Hypotension
    • The arterial blood pressure decreases in most cases, but there can be present only orthostatic hypotension [ 8 , 9 ].[hindawi.com]
    • Orthostatic hypotension and salt craving can be prominent in primary insufficiency due to aldosterone deficiency leading to profound volume depletion.[ime.acponline.org]
    • 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.[en.wikipedia.org]
    • Orthostatic hypotension, fever, and hypoglycemia characterize acute AC; whereas chronic primary AI presents with a more insidious history of malaise, anorexia, diarrhea, weight loss, joint, and back pain.[endocrinefacts.org]
    • Blood Pressure is usually low, and drops upon standing (105/60) and then elevated to (120 or 130/70 or 80) on reclining (postural or orthostatic hypotension).[drkaslow.com]
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  • urogenital
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  • Workup

    Laboratory analyses of blood samples typically yield the following results:

    Further, workup aims at identifying the cause of hypoglycemia and electrolyte imbalances and may comprise these measures [5]:

    • Conduction of an ACTH stimulation test, i.e., determination of serum cortisol levels before and after intravenous administration of synthetic ACTH. Observation of an inadequate cortisol response is consistent with AI but does not allow for a distinction between primary AI and AI due to lesions of superior centers.
    • Assessment of serum ACTH concentrations. Enhanced levels of ACTH are observed in primary AI, while secondary or tertiary AI is associated with ACTH deficiency.
    • Screening for autoantibodies directed against the adrenal tissue.
    • Diagnostic imaging to visualize neoplasms infiltrating the adrenal glands, the pituitary gland or the hypothalamus (computed tomography scans and magnetic resonance imaging).
    • Screening for gene defects known to be associated with AI.

    Treatment

    Hormone replacement is the mainstay of long-term AI therapy. A thorough workup is required to assess the degree of mineralocorticoid and glucocorticoid deficiency in individual patients, who should undergo regular follow-ups to allow for a precise adjustment of doses. In general, medication should be dosed as high as necessary and as low as possible [11].

    • Prescription of fludrocortisone is indicated in patients suffering from aldosterone deficiency. Children should receive daily doses of 0.025 to 0.2 mg per day, adults are prescribed 0.05 to 0.2 mg per day [9].
    • To compensate for glucocorticoid deficiency, adult patients are generally administered 15-25 mg hydrocortisone daily [9]. Lower doses are indicated in pediatric patients and should be based on height, weight and body surface [Park]. Under physiological conditions, glucocorticoid secretion is highest in the morning and thus, about half of the total daily dose should be administered at this time of the day. The remaining dose of hydrocortisone may be given in another two applications. Because AI patients show an inadequate cortisol response to environmental factors, it may be necessary to augment hydrocortisone dosage in periods of stress, e.g., during sickness and prior to surgery.
    • While the lack of adrenal sex steroids is compensated by testicular hormone synthesis in men, females may benefit from dehydroepiandrosterone treatment to prevent mood swings and depression, and to improve their health-related quality of life [12].

    Treatment of Addisonian crisis should be initiated immediately and comprises of high-dosed intravenous application of hydrocortisone, glucose, and saline solution. Detailed recommendations are also available [2].

    Prognosis

    Patients suffering from AI require life-long therapy unless the underlying condition is curable. In the case of non-compliance with therapeutic regimens or if left untreated, an acute metabolic decompensation may result in fatal adrenal crisis. Despite optimum therapy, the annual incidence of adrenal crisis in patients suffering from primary AI has been estimated to be about 8%, while this life-threatening complication is less frequently observed in secondary or tertiary AI [9]. Recently, Norwegian researchers found young AI patients to have an increased mortality due to adrenal failure, infection, and sudden death [10]. Otherwise, AI patients have an excellent prognosis.

    Complications

    Abetalipoproteinemia
    • Interruptions in the delivery of cholesterol include Smith-Lemli-Opitz syndrome and abetalipoproteinemia.[en.wikipedia.org]
    • Cholesterol biosynthesis disorders include Smith-Lemli-Opitz syndrome and abetalipoproteinemia, which interrupts the delivery of cholesterol as a substrate for steroidogenesis.[clinicaladvisor.com]
    Antiphospholipid Syndrome
    • […] most common infectious cause in developing countries) and sarcoidosis neoplasms: metastases (e.g. lung, ovary, kidney, melanoma), lymphoma, and leukaemia adrenal haemorrhage: shock, sepsis ( Waterhouse-Friderichsen syndrome ), coagulation disorders, antiphospholipid[radiopaedia.org]
    • Adrenal destruction is also a feature of adrenoleukodystrophy (ALD), and when the adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body, especially lung), hemorrhage (e.g. in Waterhouse-Friderichsen syndrome or antiphospholipid[en.wikipedia.org]
    • Infarction - eg, antiphospholipid syndrome.[patient.info]
    Chronic Active Hepatitis
    • Cicognani C, Malavolti M, Morselli-Labate AM, Zamboni L, Sama C, et al. (1997) Serum lipid and lipoprotein patterns in patients with liver cirrhosis and chronic active hepatitis.[omicsonline.org]
    Coccidioidomycosis
    • […] adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body, especially lung), hemorrhage (e.g. in Waterhouse-Friderichsen syndrome or antiphospholipid syndrome), particular infections (tuberculosis, histoplasmosis, coccidioidomycosis[en.wikipedia.org]
    • CT of the adrenals will establish whether there are calcifications due to granulomatous diseases (e.g. tuberculosis, histoplasmosis, coccidioidomycosis), or adrenal hemorrhage (due to Coumadin or heparin), or metastatic adrenal disease (lung, pancreas[endocrinologyadvisor.com]
    Dehydration
    • Moderate dehydration: Normal saline 10 ml/kg i.v. bolus.[rch.org.au]
    • EMERGENCY If you have been diagnosed with Addison’s disease and experience symptoms of severe lethargy, nausea, vomiting, dizziness, or dehydration, get immediate medical assistance.[healthcommunities.com]
    • […] enough hormones As a result of long-term steroid use Symptoms of adrenal insufficiency include: Nausea or vomiting Cold, clammy skin Fast heart beat or fast breathing Weakness, dizziness, paleness Confusion Dry mouth, thirsty, decrease in urine (signs of dehydration[cincinnatichildrens.org]
    • […] axis over time most common cause: administration of exogenous glucortiocoids mechanism: chronic ACTH suppression - adrenal atrophy ADRENAL CRISIS concurrent illness, surgery, failure to take medications GI: abdominal pain, vomiting and diarrhoea CVS: dehydration[lifeinthefastlane.com]
    • That can happen for many reasons, such as an illness, fever, surgery, or dehydration.[hopkinsmedicine.org]
    Disseminated Histoplasmosis
    Hemochromatosis
    • Minor causes of chronic adrenal insufficiency are systemic amyloidosis, fungal infections, hemochromatosis, and sarcoidosis.[en.wikipedia.org]
    • […] immunosuppressed states (especially AIDS ) Adrenal hemorrhage [1] Waterhouse‑Friderichsen syndrome : meningococcal sepsis hemorrhagic necrosis Infiltration of the adrenal glands Tumors (adrenocortical tumors, lymphomas, metastatic carcinoma) Amyloidosis Hemochromatosis[amboss.com]
    • ) Neoplastic destruction Metabolic disorders (eg, various forms of adrenal leukodystrophy [OMIM 300100], [13, 14 ] Wolman disease [OMIM 278000 ], Smith-Lemli-Opitz syndrome [OMIM 270400] [15] ) Administration of the anesthetic agent etomidate [ 16 ] Hemochromatosis[emedicine.medscape.com]
    • Hemochromatosis does not explain the other symptoms this patient is experiencing.[medbullets.com]
    Hypoglycemia
    • […] when there is more than 90% destruction of the adrenal gland Clinical features Often insidious in onset, patients may present in shock due to increased stress Malaise, lassitude, fatigue, weakness, anorexia, weight loss, nausea, vomiting, hypotension, hypoglycemia[pathologyoutlines.com]
    • Hypoadrenalism was suspected as severe hypoglycemia did not respond to continuous ev glucose administration.[bloodjournal.org]
    • Patients with panhypopituitarism have depressed thyroid and gonadal function and hypoglycemia.[merckmanuals.com]
    • Hypoglycemia is most common in young children.[clinicaladvisor.com]
    • Fluid replacement ; with normal saline to treat hypotension ; and hyponatremia Correct hypoglycemia , hyperkalemia and metabolic acidosis .[amboss.com]
    Hypotension
    • Hypotension as a result of hypovolaemia is present in 80-90% of cases, however, in may cases the hypotension is only postural and systolic.[almostadoctor.co.uk]
    • 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.[en.wikipedia.org]
    • , refractory shock, poor response to inotropes/pressors fever confusion CHRONIC ADRENAL INSUFFICIENCY GENERAL: weight loss, arthalgia, myalgia CNS: fatigue, anorexia, mood change CVS: postural hypotension, syncope, salt craving SKIN: pigmentation, vitiligo[lifeinthefastlane.com]
    • Fluid replacement ; with normal saline to treat hypotension ; and hyponatremia Correct hypoglycemia , hyperkalemia and metabolic acidosis .[amboss.com]
    Systemic Amyloidosis
    • Minor causes of chronic adrenal insufficiency are systemic amyloidosis, fungal infections, hemochromatosis, and sarcoidosis.[en.wikipedia.org]
    Triple A Syndrome
    • […] unresponsiveness may be isolated (as in Familial Glucocorticoid Deficiency ) (Online Mendelian Inheritance in Man database [OMIM] 202200 ), [7, 8 ] or it may be associated with achalasia and alacrima (as in achalasia-addisonism-alacrima syndrome, or triple[emedicine.medscape.com]
    • In the instance that adrenocortical deficiency occurs along with other presentations such as achalasia and alacrimia, the syndrome is called Allgrove or triple A syndrome. 2.[clinicaladvisor.com]
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  • Etiology

    AI is a general term that may refer to distinct entities.

    Patients may suffer from primary AI, i.e., dysfunction of the adrenal glands results in a decreased production of adrenal hormones. Generally, this form of AI comprises all zones of the adrenal cortex and the adrenal medulla and thus, patients suffer from both mineralocorticoid and glucocorticoid deficiencies. Possible causes of primary AI are adrenal dysgenesis, congenital adrenal hyperplasia due to hereditary enzyme deficiencies, ACTH resistance syndromes, metabolic disorders interfering with cholesterol synthesis or peroxisomal function, isolated autoimmune adrenalitis, autoimmune polyendocrinopathy, infectious diseases like tuberculosis, adrenal infarction, adrenal hemorrhage, trauma, neoplasms, drug-induced AI and surgical resection [1]. Of note, clinical symptoms may only manifest after the destruction of the vast majority of adrenal tissue [2].

    Secondary and tertiary AI are provoked by lesions of superior centers. Both glucocorticoid- and androgen-producing cells form part of the hypothalamic-pituitary-adrenal hormone axis, i.e., the corresponding subpopulations of adrenal cells depend on the release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and the anterior pituitary gland, respectively. The hypothalamic and pituitary function may be impaired by ischemia or stroke, inflammation, and/or infection, trauma, benign and malignant neoplasms, long-term administration of glucocorticoids and irradiation of the brain, among others. In contrast, mineralocorticoid release is not affected by CRH and ACTH levels but is regulated by the renin-angiotensin system. Thus, individuals affected by secondary or tertiary AI don't develop mineralocorticoid deficiency.

    Of note, partial dysfunction of the adrenal glands is also observed in pathologies that are usually not considered forms of AI. For instance, the adrenogenital syndrome is caused by a gene defect resulting in reduced adrenal glucocorticoid synthesis, consequently increased ACTH levels, and an excess stimulation of adrenal androgen production [3]. Isolated hypoaldosteronism is rare but may occur in patients suffering from chronic idiopathic hypoaldosteronism, familial corticosterone methyl oxidase deficiencies, persistent hypotension or conditions associated with reduced renin secretion [4].

    Epidemiology

    Autoimmune-mediated AI is the most common form of the disease and its prevalence has been estimated to 1 in 10,000 people. Congenital adrenal hyperplasia is diagnosed in 1 per 15,000 life births, and about 1 in 20,000 men suffers from X-linked adrenoleukodystrophy [5]. The annual incidence of primary AI has been stated to be <1 in 100,000 inhabitants of western Norway[6], and this condition is most frequently diagnosed during the fourth decade of life. Of note, symptom onset of congenital adrenal hyperplasia and X-linked adrenoleukodystrophy typically occurs in infancy or childhood [7].

    AI due to disturbances of the hypothalamic-pituitary-adrenal hormone axis is more common than primary AI affects up to 28 per 100,000 people and is most commonly a side effect of prolonged glucocorticoid therapy [8]. Women are affected more often than men. Contrary to primary AI, it is usually diagnosed in the elderly.

    Sex distribution
    Age distribution

    Pathophysiology

    The adrenal cortex encapsulates the adrenal medulla and consists of three layers denominated zona glomerulosa, zona fasciculata, and zona reticularis. Distinct subpopulations of adrenal cells produce hormones that affect electrolyte balance, carbohydrate metabolism, growth and sexual characteristics, as well as autonomous functions. In detail, the following hormones originate from the adrenal glands:

    • Zona glomerulosa: aldosterone
    • Zona fasciculata: glucocorticoids like cortisol and corticosterone
    • Zona reticularis: sex steroids, e.g., dehydroepiandrosterone which is subsequently converted to androgens and estrogens
    • Adrenal medulla: epinephrine and norepinephrine

    AI is primarily associated with disturbances of electrolyte balance and carbohydrate metabolism, since deficiencies in adrenal androgen and catecholamine production are largely compensated by the testes, chromaffin paraganglia, and the sympathetic nervous system, respectively.

    Aldosterone acts on renal tubular epithelial cells, mucous membranes of the intestinal tract, salivary and sweat glands. It favors the excretion of potassium and protons and stimulates the reabsorption of sodium, chloride, and water in distal tubules of the kidneys by inducing an up-regulation of ion channel and Na+-K+-ATPase expression. Consequently, patients suffering from AI with mineralocorticoid deficiency develop hyperkalemia, metabolic acidosis, hyponatremia, hypochloremia, and hypovolemia.

    Glucocorticoid release provokes an increase of serum glucose levels by enhancing hepatic gluconeogenesis and induction of peripheral insulin resistance. At the same time, glucocorticoids favor protein and lipid catabolism. Lack of glucocorticoids thus leads to hypoglycemia, insulin sensitivity, and weight loss. Of note, ACTH secretion is physiologically reduced by glucocorticoids, but this negative feedback loop is interrupted in AI. Thus, pituitary ACTH synthesis is permanently elevated and this condition results in increased levels of the melanocyte-stimulating hormone, which originates from the same precursor (proopiomelanocortin; POMC). Therefore, AI patients develop hyperpigmentation of the skin.

    Prevention

    Long-term administration of glucocorticoids should be avoided; if required, doses should be maintained as low as possible. Further measures can be undertaken to avoid traumatic lesions of the adrenal glands, pituitary gland, and hypothalamus; excision during retroperitoneal and head surgery; and infectious diseases that may affect these endocrine organs. No specific measures can be recommended to prevent autoimmune-mediated AI.

    Summary

    Healthy adrenal glands release a variety of hormones, namely mineralocorticoids, glucocorticoids, estrogen, progesterone, and catecholamines. Adrenal insufficiency (AI) may refer to a reduced production of either or all of those hormones, and this condition may be provoked by distinct diseases. On the one hand, pathologies may directly affect adrenal tissues and thus interfere with hormone synthesis. This form of AI is deemed primary AI and may also be referred to as Addison's disease. Most cases of primary AI are the result of an autoimmune disease. On the other hand, the adrenal glands form part of the complex endocrine network and are subjected to regulatory mechanisms. Thus, functional impairment of superior centers may be associated with an inadequate stimulation of adrenal hormone synthesis. In detail, lesions of the pituitary gland may cause secondary AI, lesions of the hypothalamus may trigger tertiary AI. Therapy is mainly symptomatic and consists in life-long supplementation of mineralocorticoids and glucocorticoids. If the underlying disease is curable, the patient's prognosis improves.

    Patient Information

    The adrenal glands are endocrine organs located in close proximity to the kidneys. They are composed of distinct subpopulations of cells which release hormones that affect electrolyte balance, carbohydrate metabolism, growth and sexual characteristics, as well as autonomous function. If an individual suffers from adrenal insufficiency (AI), adrenal hormone production is partially or completely impaired. Since the adrenal glands form part of the complex endocrine network, they are subjected to regulatory mechanisms. Therefore, AI may not only result from a dysfunction of adrenal tissue (e.g., due to developmental or gene defects, or owing to destruction of the adrenal glands in an immune reaction directed against endogenous tissues), but also from lesions of superior centers. Those superior centers are located within or close to the brain and may be affected by stroke, trauma, tumors and other pathologies. Furthermore, regulatory mechanisms may be overridden if certain drugs, mainly glucocorticoids, are administered over long periods of time.

    AI patients typically experience fatigue, lethargy, generalized weakness, hypotension, postural dizziness, nausea, vomiting and diarrhea, loss of appetite and weight, and hyperpigmentation. Laboratory analyses of blood samples typically reveal hyponatremia, hypochloremia, hyperkalemia, and metabolic acidosis. In order to prevent so-called adrenal crisis, which are life-threatening events resulting from an acute metabolic decompensation, missing hormones have to be supplemented. Accordingly, affected individuals require life-long therapy with fludrocortisone and/or hydrocortisone. Compliance with therapeutic regimens provided, AI patients have an excellent prognosis.

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    References

    1. Park J, Didi M, Blair J. The diagnosis and treatment of adrenal insufficiency during childhood and adolescence. Arch Dis Child. 2016; 101(9):860-865.
    2. Naziat A, Grossman A. Adrenal Insufficiency. In: De Groot LJ, Beck-Peccoz P, Chrousos G, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000.
    3. Díez López I, Rodríguez Estévez A, González Molina E, Martínez Ayucar M, Rodríguez Pérez B, Ezquieta Zubicaray B. [Virilizing congenital adrenogenital syndrome with a de novo I172N mutation: study of a new case]. An Pediatr (Barc). 2010; 72(1):72-78.
    4. Talapatra I, Kalavalapalli S, Tymms DJ. Isolated hypoaldosteronism: An overlooked cause of hyponatraemia. Eur J Intern Med. 2007; 18(3):246-248.
    5. Neary N, Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes. 2010; 17(3):217-223.
    6. Løvås K, Husebye ES. High prevalence and increasing incidence of Addison's disease in western Norway. Clin Endocrinol (Oxf). 2002; 56(6):787-791.
    7. Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med. 2009; 360(22):2328-2339.
    8. Wallace I, Cunningham S, Lindsay J. The diagnosis and investigation of adrenal insufficiency in adults. Ann Clin Biochem. 2009; 46(Pt 5):351-367.
    9. Yanase T, Tajima T, Katabami T, et al. Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion]. Endocr J. 2016.
    10. Erichsen MM, Lovas K, Fougner KJ, et al. Normal overall mortality rate in Addison's disease, but young patients are at risk of premature death. Eur J Endocrinol. 2009; 160(2):233-237.
    11. Simunkova K, Husebye ES. Adrenal Insufficiency Therapy: How to Keep the Balance between Good Quality of Life and Low Risk for Long-Term Side Effects? Front Horm Res. 2016; 46:196-210.
    12. Alkatib AA, Cosma M, Elamin MB, et al. 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. 2009; 94(10):3676-3681.



    Media References

    1. Illu adrenal gland, Public Domain

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