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Adrenal Insufficiency

Adrenal Failure

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.

Fatigue
  • Abstract A 78-year-old Japanese man with fatigue, appetite loss, skin hyperpigmentation, hypotension and hypoglycemia, visited our hospital to evaluate an abnormal chest X-ray and adrenal gland swelling in echography in February 2015.[ncbi.nlm.nih.gov]
  • However, his appetite and fatigue did not improve over time and he was readmitted for an examination.[ncbi.nlm.nih.gov]
  • Abstract Primary adrenal insufficiency (AI) in children usually presents with non-specific symptoms such as fatigue, nausea, vomiting, and anorexia.[ncbi.nlm.nih.gov]
  • A fatigued 8-year-old boy was found to have sideroblastic anaemia (haemoglobin 7.8 g/dL) which over time became transfusion dependent.[ncbi.nlm.nih.gov]
  • CASE REPORT: A 60-year-old woman with a past medical history of Cushing's syndrome developed hyponatremia with symptoms of acute glucocorticoid deficiency, such as prolonged general fatigue and anorexia, after upper respiratory tract infection.[ncbi.nlm.nih.gov]
Weakness
  • The presenting symptoms can be non-specific (as in this patient) and easily confused with other common sequelae of ASCI such as orthostasis and diffuse weakness.[ncbi.nlm.nih.gov]
  • The perioperative phase was characterised by hypotension and sputum stasis due to muscle weakness, which caused two readmissions to the intensive care unit. His physical examination showed two fully rigid auricles.[ncbi.nlm.nih.gov]
  • CASE PRESENTATION: A 52-year-old Caucasian woman presented with abdominal pain, vomiting and weakness nine days after arthroplasty and heparin use.[ncbi.nlm.nih.gov]
  • A 40-year-old woman presented with depression, general weakness and anorexia. Laboratory tests and imaging studies were compatible with liver cirrhosis due to Wilson's disease.[ncbi.nlm.nih.gov]
  • After arbitrary reintroduction of macrogol, the child presented with hypoglycaemia, lethargy, weakness, and hypotonia; ACTH was 3145 ng/L. After again stopping macrogol, her ACTH was near normalized (323 ng/L).[ncbi.nlm.nih.gov]
Weight Loss
  • A 72-year-old man presented with weight loss, night sweats and haemoptysis and was hypotensive. CT imaging showed rapidly enlarging bilateral adrenal masses, and he was found to have primary adrenal insufficiency.[ncbi.nlm.nih.gov]
  • He had a 3-month history of left flank pain, nausea and vomiting with weight loss. A CT scan at a private hospital revealed bilateral large adrenal masses; the patient was referred to our centre based on these findings.[ncbi.nlm.nih.gov]
  • CASE PRESENTATION: We present the case of a 68-year-old Caucasian male who underwent a thymoma resection and suffered from preoperative weight loss and lack of strength.[ncbi.nlm.nih.gov]
  • We describe the case of an 83-year-old woman admitted to the emergency department due to a month's history of asthenia, weight loss, anorexia and nausea.[ncbi.nlm.nih.gov]
  • Symptoms are the same as for Addison disease and include fatigue, weakness, weight loss, nausea, vomiting, and diarrhea, but there is usually less hypovolemia.[merck.com]
Collapse
  • RATIONALE: Late-onset transient adrenal insufficiency with circulatory collapse is a rare condition that occurs in preterm infants.[ncbi.nlm.nih.gov]
  • BACKGROUND: Primary adrenal insufficiency is relatively rare in children and, if unrecognized, may present with cardiovascular collapse, making it a potentially life-threatening entity.[ncbi.nlm.nih.gov]
  • If unrecognized, adrenal insufficiency may present with life-threatening cardiovascular collapse.[pediatrics.aappublications.org]
  • 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]
Constitutional Symptom
  • Abstract A 66-year-old man, chronic smoker, presented with episodes of syncope, hypotension and constitutional symptoms.[ncbi.nlm.nih.gov]
Vomiting
  • Abstract Primary adrenal insufficiency (AI) in children usually presents with non-specific symptoms such as fatigue, nausea, vomiting, and anorexia.[ncbi.nlm.nih.gov]
  • He had a 3-month history of left flank pain, nausea and vomiting with weight loss. A CT scan at a private hospital revealed bilateral large adrenal masses; the patient was referred to our centre based on these findings.[ncbi.nlm.nih.gov]
  • He also had increased pigmentation of body and persistent vomiting since six months of age. Laboratory investigations and imaging revealed alacrimia, achalasia and adrenal insufficiency due to ACTH resistance.[ncbi.nlm.nih.gov]
  • CASE PRESENTATION: A 52-year-old Caucasian woman presented with abdominal pain, vomiting and weakness nine days after arthroplasty and heparin use.[ncbi.nlm.nih.gov]
  • A 45-year-old woman with a history of NS presented 2 weeks after abrupt cessation of prednisone with nausea, vomiting, decreased oral intake and confusion. She was diagnosed with secondary AI and intravenous hydrocortisone was promptly begun.[ncbi.nlm.nih.gov]
Nausea
  • Abstract Primary adrenal insufficiency (AI) in children usually presents with non-specific symptoms such as fatigue, nausea, vomiting, and anorexia.[ncbi.nlm.nih.gov]
  • He had a 3-month history of left flank pain, nausea and vomiting with weight loss. A CT scan at a private hospital revealed bilateral large adrenal masses; the patient was referred to our centre based on these findings.[ncbi.nlm.nih.gov]
  • We describe the case of an 83-year-old woman admitted to the emergency department due to a month's history of asthenia, weight loss, anorexia and nausea.[ncbi.nlm.nih.gov]
  • A 45-year-old woman with a history of NS presented 2 weeks after abrupt cessation of prednisone with nausea, vomiting, decreased oral intake and confusion. She was diagnosed with secondary AI and intravenous hydrocortisone was promptly begun.[ncbi.nlm.nih.gov]
  • Symptoms are the same as for Addison disease and include fatigue, weakness, weight loss, nausea, vomiting, and diarrhea, but there is usually less hypovolemia.[merck.com]
Diarrhea
  • Abstract Diarrhea following organ transplantation is usually associated with infection and immunosuppression therapy.[ncbi.nlm.nih.gov]
  • Discuss with your doctor the need for adequate glucocorticoid replacement if you are having surgery, major dental work, or other invasive procedures or if you are sick with a fever, vomiting, or diarrhea.[doi.org]
  • Symptoms are the same as for Addison disease and include fatigue, weakness, weight loss, nausea, vomiting, and diarrhea, but there is usually less hypovolemia.[merck.com]
  • Abstract A 63-year-old woman who had hypopituitarism was re-admitted to our hospital because of fever, diarrhea and disturbance of consciousness with life-threatening arrhythmia due to prolongation of the QT interval.[ncbi.nlm.nih.gov]
Hypotension
  • KEYWORDS: Adrenal insufficiency; corticosteroid therapy; hypotension; nocturnal home hemodialysis[ncbi.nlm.nih.gov]
  • Nevertheless, it can be suspected in patients who enter the emergency room with complaints of abdominal pain, hypotension unresponsive to volume or vasopressor agents, clouding, and torpor.[ncbi.nlm.nih.gov]
  • Abstract A 78-year-old Japanese man with fatigue, appetite loss, skin hyperpigmentation, hypotension and hypoglycemia, visited our hospital to evaluate an abnormal chest X-ray and adrenal gland swelling in echography in February 2015.[ncbi.nlm.nih.gov]
  • A 72-year-old man presented with weight loss, night sweats and haemoptysis and was hypotensive. CT imaging showed rapidly enlarging bilateral adrenal masses, and he was found to have primary adrenal insufficiency.[ncbi.nlm.nih.gov]
  • Abstract A 66-year-old man, chronic smoker, presented with episodes of syncope, hypotension and constitutional symptoms.[ncbi.nlm.nih.gov]
Orthostatic Hypotension
  • 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]
  • 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.[symptoma.com]
  • hypotension, nausea, vomiting, diarrhea, hyponatremia, hypoglycemia, mild anemia, increased WBCs, eosinophilia 2 0 adrenal insufficiency Pallor of skin, amenorrhea, libido, axillary and pubic hair, small testicles, 2º hyperthyroidism, defect in prepubertal[medical-dictionary.thefreedictionary.com]
Hyperpigmentation
  • PATIENT AND METHODS: The patient was born with hyperpigmentation, micropenis, penoscrotal hypospadias, and mild cryptorchidism. Biochemical and hormonal findings were normal except for low testosterone and low-borderline cortisol.[ncbi.nlm.nih.gov]
  • This situation may be associated with symptoms suggestive of chronic adrenal insufficiency such as hyperpigmentation, salt craving, and association with autoimmune diseases such as vitiligo and Hashimoto's thyroiditis.[ncbi.nlm.nih.gov]
  • Addison disease was identified due to hyperpigmentation of lips and gums present from early childhood. This is the first report describing adrenal insufficiency in a child with MELAS phenotype. Copyright 2014 The Japanese Society of Child Neurology.[ncbi.nlm.nih.gov]
  • Unlike in Addison disease, hyperpigmentation does not occur and serum sodium and potassium levels are relatively normal. ACTH and cortisol levels both are low.[merck.com]
  • She was presented with skin hyperpigmentation of her face, neck, upper limbs, buccal mucosa and lips, which worsened when commenced on 6-mercaptopurine treatment for prophylaxis of postoperative recurrence.[ncbi.nlm.nih.gov]
Myalgia
  • 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]
  • Other symptoms may include weight loss, anorexia , myalgia, dizziness, fainting. There may also be low self-esteem and depression .[almostadoctor.co.uk]
  • Early signs of this medical emergency include malaise, weakness, and myalgias. As cortisol levels remain low, patients may develop severe hypotension, vascular collapse, acute renal failure, and hypothermia.[pharmacytimes.com]
  • Myalgia and arthralgia may also be experienced.[symptoma.com]
  • […] 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]
Flexion Contracture
  • Abstract Patients with acute adrenal insufficiency may have musculoskeletal symptoms including flexion contractures, myopathy and hyperkalaemic neuromyopathy.[ncbi.nlm.nih.gov]
Vertigo
  • Other symptoms include vertigo, hypotension, depression, salt craving, and vitiligo (depigmented patches of skin).[pharmacytimes.com]
  • […] onset Autoimmune disease, TB, adrenomyeloneuropathy, systemic fungal infection, metastatic cancer, AIDS-related-eg Kaposi sarcoma, CMV Clinical Symptoms shared with 2 0 adrenal insufficiency Tiredness, weakness, mental depression, anorexia, weight loss, vertigo[medical-dictionary.thefreedictionary.com]

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.
Liver Biopsy
  • The most likely pathophysiology of acute liver injury was DILI, given the clinical course of liver injury and the liver biopsy result of non-caseating granulomas.[ncbi.nlm.nih.gov]

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.

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.

References

Article

  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.

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Last updated: 2018-06-22 01:58