Adrenal Insufficiency and Addison Disease (Clinical)

Overview

Definition^[6,7]

Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease (AI) is the deficiency in adrenal production of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids, adrenal androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens, and mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids.

Forms of adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease^[6,7]

• Primary (Addison disease): dysfunction or destruction of the adrenal cortex Adrenal Cortex The outer layer of the adrenal gland. It is derived from mesoderm and comprised of three zones (outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis) with each producing various steroids preferentially, such as aldosterone; hydrocortisone; dehydroepiandrosterone; and androstenedione. Adrenal cortex function is regulated by pituitary adrenocorticotropin. Adrenal Glands: Anatomy
• Secondary: conditions that cause deficiency in pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types adrenocorticotropic hormone Adrenocorticotropic hormone An anterior pituitary hormone that stimulates the adrenal cortex and its production of corticosteroids. Acth is a 39-amino acid polypeptide of which the n-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotropic activity. Upon further tissue-specific processing, acth can yield alpha-msh and corticotropin-like intermediate lobe peptide (clip). Adrenal Hormones (ACTH) secretion Secretion Coagulation Studies
• Tertiary: conditions that cause deficiency in the hypothalamic secretion Secretion Coagulation Studies of corticotropin-releasing hormone Corticotropin-releasing hormone A peptide of about 41 amino acids that stimulates the release of adrenocorticotropic hormone. Crh is synthesized by neurons in the paraventricular nucleus of the hypothalamus. After being released into the pituitary portal circulation, crh stimulates the release of acth from the pituitary gland. Crh can also be synthesized in other tissues, such as placenta; adrenal medulla; and testis. Hypothalamic and Pituitary Hormones (CRH)

Epidemiology^[6,7]

• Annual incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 4–6 cases per million people
• Secondary AI Secondary AI Deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion. Adrenal Insufficiency and Addison Disease is more common than primary adrenal disorders.
• Autoimmune AI affects women more often than men.
• Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are diagnosed in the 6th decade of life.
• Hospitalizations have increased in recent decades:^[8]
  • Admissions for AI (mostly secondary): ↑ 62% between 2000 and 2019 (from 36.8/million to 59.6/million)
  • Admissions for adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison Disease: ↑ 90% (from 10.7/million to 20.4/million)

Etiology

Etiology of primary adrenal insufficiency Primary adrenal insufficiency An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease^[2,5,14]

Primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease is caused by processes that affect the adrenal gland’s ability to produce cortisol Cortisol Glucocorticoids. The most common cause is idiopathic Idiopathic Dermatomyositis autoimmune destruction (adrenalitis).

• Idiopathic Idiopathic Dermatomyositis autoimmune destruction (80%)
• Autoimmune polyendocrine syndrome type I Autoimmune polyendocrine syndrome type I Adrenal Insufficiency and Addison Disease (APECED (autoimmune polyendocrinopathy, candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis, ectodermal dystrophy) syndrome):
  • Addison disease
  • Chronic mucocutaneous candidiasis Chronic mucocutaneous candidiasis A clinical syndrome characterized by development, usually in infancy or childhood, of a chronic, often widespread candidiasis of skin, nails, and mucous membranes. It may be secondary to one of the immunodeficiency syndromes, inherited as an autosomal recessive trait, or associated with defects in cell-mediated immunity, endocrine disorders, dental stomatitis, or malignancy. Adaptive Immune Response
  • Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism
  • Primary gonadal failure
  • Hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS) of the dental enamel Enamel A hard thin translucent layer of calcified substance which envelops and protects the dentin of the crown of the tooth. It is the hardest substance in the body and is almost entirely composed of calcium salts. Under the microscope, it is composed of thin rods (enamel prisms) held together by cementing substance, and surrounded by an enamel sheath. Teeth: Anatomy 
  • Nail dystrophy
• Autoimmune polyendocrine syndrome type II Autoimmune polyendocrine syndrome type II Adrenal Insufficiency and Addison Disease:
  • Addison disease
  • Primary hypothyroidism Primary Hypothyroidism Hypothyroidism
  • Primary hypogonadism Primary Hypogonadism Myotonic Dystrophies
  • Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus type 1 Type 1 Spinal Muscular Atrophy
  • Pernicious anemia Pernicious anemia A megaloblastic anemia occurring in children but more commonly in later life, characterized by histamine-fast achlorhydria, in which the laboratory and clinical manifestations are based on malabsorption of vitamin B12 due to a failure of the gastric mucosa to secrete adequate and potent intrinsic factor. Megaloblastic Anemia
  • Vitiligo Vitiligo Vitiligo is the most common depigmenting disorder and is caused by the destruction of melanocytes. Patients present with hypo- or depigmented macules or patches which often occur on the face, hands, knees, and/or genitalia. Vitiligo
  • Celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease
• Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease that replace adrenal tissue (15%):
  • Tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
  • Fungal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease ( coccidioidomycosis Coccidioidomycosis Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Coccidioides/Coccidioidomycosis, histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis)
  • Cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus
  • HIV HIV Anti-HIV Drugs
• Infiltrative disease of the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands: Anatomy:
  • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis
  • Amyloid
  • Hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis
• Malignancies affecting the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands: Anatomy:
  • Metastases from lung, breast, renal, or GI primary tumors
  • Lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
• Intra-adrenal hemorrhage Intra-adrenal hemorrhage A condition of hemorrhage and necrosis of the adrenal gland. It is characterized by rapidly developing adrenal insufficiency; hypotension; and widespread cutaneous purpura. Adrenal Insufficiency and Addison Disease:
  • Waterhouse–Friderichsen syndrome Waterhouse–Friderichsen syndrome A condition of hemorrhage and necrosis of the adrenal gland. It is characterized by rapidly developing adrenal insufficiency; hypotension; and widespread cutaneous purpura. Adrenal Insufficiency and Addison Disease after meningococcal septicemia
  • Antiphospholipid syndrome Antiphospholipid syndrome Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome
  • Heparin-induced thrombocytopenia Heparin-Induced Thrombocytopenia Thrombocytopenia (HIT) 
• Adrenoleukodystrophies: rare X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) condition (1:25,000)
• Congenital adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation:
  • Mutations of the 21-hydroxylase (CYP21A2) or 11 beta-hydroxylase (CYP11B1) genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure → nearly complete deficiency of an enzyme required for cortisol Cortisol Glucocorticoids synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Presents in infancy with adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease and salt-wasting crisis
• ACTH resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing syndromes (familial glucocorticoid resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing)
• Bilateral adrenalectomy Adrenalectomy Excision of one or both adrenal glands. Cushing Syndrome
• Drug-induced (inhibit cortisol Cortisol Glucocorticoids synthesis Synthesis Polymerase Chain Reaction (PCR) by the adrenal gland):
  • Mitotane
  • Ketoconazole Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Azoles
  • Fluconazole Fluconazole Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in aids. Azoles
  • Etomidate Etomidate Imidazole derivative anesthetic and hypnotic with little effect on blood gases, ventilation, or the cardiovascular system. It has been proposed as an induction anesthetic. Intravenous Anesthetics
  • Suramin
  • Aminoglutethimide

Etiology of secondary and tertiary adrenal insufficiency Tertiary adrenal insufficiency Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease^[2,4,14]

Secondary and tertiary AI Tertiary AI Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease are a consequence of dysfunction of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus and pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland. Secondary AI Secondary AI Deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion. Adrenal Insufficiency and Addison Disease is most often due to glucocorticoid therapy in greater than physiologic doses, used for treating rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis, inflammatory bowel disease, and severe asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma.

Secondary:

• Hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism
  • Pituitary tumors Pituitary tumors Neoplasms which arise from or metastasize to the pituitary gland. The majority of pituitary neoplasms are adenomas, which are divided into non-secreting and secreting forms. Hormone producing forms are further classified by the type of hormone they secrete. Pituitary adenomas may also be characterized by their staining properties. Pituitary tumors may compress adjacent structures, including the hypothalamus, several cranial nerves, and the optic chiasm. Chiasmal compression may result in bitemporal hemianopsia. Pituitary Adenomas, irradiation, and surgery
  • Granulomatous/infiltrative disease ( tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, sarcoid, eosinophilic granuloma)
  • Postpartum pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types infarction ( Sheehan’s syndrome Sheehan’s syndrome Postpartum pituitary necrosis caused by blood loss during childbirth. Hypopituitarism)
• Medications:
  • Exogenous glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids 
  • Long-term and high-dose opiates Opiates Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
  • Immunotherapies for malignancy Malignancy Hemothorax → hypophysitis with selective loss of ACTH secretion Secretion Coagulation Studies:
    • Ipilimumab 
    • Nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma 
    • Pembrolizumab Pembrolizumab Squamous Cell Carcinoma (SCC)
  • High-dose progestins Progestins Compounds that interact with progesterone receptors in target tissues to bring about the effects similar to those of progesterone. Primary actions of progestins, including natural and synthetic steroids, are on the uterus and the mammary gland in preparation for and in maintenance of pregnancy. Hormonal Contraceptives (e.g., megestrol acetate Megestrol acetate Megestrol acetate is a progestogen with actions and uses similar to those of the progestogens in general. It also has anti-androgenic properties. It is given by mouth in the palliative treatment or as an adjunct to other therapy in endometrial carcinoma and in breast cancer. Noncontraceptive Estrogen and Progestins for metastatic breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer)
• Isolated ACTH deficiency:
  • Lymphocytic hypophysitis Lymphocytic Hypophysitis Adrenal Insufficiency and Addison Disease (selective corticotroph absence)
  • POMC gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations
  • TPIT gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations
• Familial cortisol-binding globulin deficiency

Tertiary:

• Prolonged high-dose glucocorticoid use
• Effect of Cushing syndrome Cushing syndrome A condition caused by prolonged exposure to excess levels of cortisol (hydrocortisone) or other glucocorticoids from endogenous or exogenous sources. It is characterized by upper body obesity; osteoporosis; hypertension; diabetes mellitus; hirsutism; amenorrhea; and excess body fluid. Endogenous Cushing syndrome or spontaneous hypercortisolism is divided into two groups, those due to an excess of adrenocorticotropin and those that are acth-independent. Paraneoplastic Syndromes treatment:
  • Chronic elevation of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids (e.g., from tumor Tumor Inflammation effects) has suppressed the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus– pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types–adrenal axis.
  • The patient still has low cortisol Cortisol Glucocorticoids levels (due to chronic suppression Suppression Defense Mechanisms) up to a year after surgery and requires glucocorticoid therapy.

Pathophysiology

Primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease due to autoimmune destruction is most often caused by serum antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions against steroidogenic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, most commonly P450c21 (CYP21A2, 21-hydroxylase) and occasionally others. The pathophysiology in all cases involves the lack of mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids and glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids needed to promote sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia retention and enhance vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure. 

Hormonal regulation^[1,6,7]

• Hypothalamic– pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types–adrenal (HPA) axis:
  • Hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus secretes CRH → release of ACTH from the anterior pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland
  • ACTH release:
    • Like CRH, release is pulsatile, following the circadian rhythm Circadian Rhythm The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs or environmental and physiological stimuli. Cranial Nerve Palsies.
    • ↑ in the early morning hours (before awakening), with peak levels in the morning (approximately 8:30 a.m.) and ↓ in the evening
  • Adrenal gland (cortex):
    •  ACTH mainly stimulates the zona fasciculata Zona Fasciculata The wide middle zone of the adrenal cortex. This zone produces a series of enzymes that convert pregnenolone to cortisol (hydrocortisone) via 17-alpha-hydroxyprogesterone. Adrenal Glands: Anatomy ( cortisol Cortisol Glucocorticoids) and zona reticularis Zona Reticularis The inner zone of the adrenal cortex. This zone produces the enzymes that convert pregnenolone, a 21-carbon steroid, to 19-carbon steroids (dehydroepiandrosterone; and androstenedione) via 17-alpha-hydroxypregnenolone. Adrenal Glands: Anatomy ( androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens).
    • The zona glomerulosa Zona Glomerulosa The narrow subcapsular outer zone of the adrenal cortex. This zone produces a series of enzymes that convert pregnenolone to aldosterone. The final steps involve three successive oxidations by cytochrome p-450 cyp11b2. Adrenal Glands: Anatomy ( aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia) is primarily regulated by the renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation–angiotensin system and potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia levels.
• Cortisol Cortisol Glucocorticoids:
  • Metabolic effects:
    • ↓  Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance uptake by cells and ↑ gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis
    • ↑  Lipolysis Lipolysis The metabolic process of breaking down lipids to release free fatty acids, the major oxidative fuel for the body. Lipolysis may involve dietary lipids in the digestive tract, circulating lipids in the blood, and stored lipids in the adipose tissue or the liver. A number of enzymes are involved in such lipid hydrolysis, such as lipase and lipoprotein lipase from various tissues. Nonalcoholic Fatty Liver Disease → release of fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance into the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment
    • ↓ Protein storage → myopathy Myopathy Dermatomyositis, bone resorption Bone resorption Bone loss due to osteoclastic activity. Bones: Remodeling and Healing
  • ↑ Smooth muscle (vasculature) sensitivity to catecholamines Catecholamines A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. Adrenal Hormones and angiotensin II Angiotensin II An octapeptide that is a potent but labile vasoconstrictor. It is produced from angiotensin I after the removal of two amino acids at the c-terminal by angiotensin converting enzyme. The amino acid in position 5 varies in different species. To block vasoconstriction and hypertension effect of angiotensin II, patients are often treated with ace inhibitors or with angiotensin II type 1 receptor blockers. Renal Sodium and Water Regulation (producing ↑ blood pressure)
  • Antiinflammatory actions:
    • Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage of T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions
    • ↓ Antibody production
    • ↓ Neutrophil migration
• Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens:
  • Dehydroepiandrosterone Dehydroepiandrosterone A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (DHEA) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens ( DHEA DHEA A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (dhea) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens) and DHEA DHEA A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (dhea) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens sulfate (DHEA-S) from the adrenal cortex Adrenal Cortex The outer layer of the adrenal gland. It is derived from mesoderm and comprised of three zones (outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis) with each producing various steroids preferentially, such as aldosterone; hydrocortisone; dehydroepiandrosterone; and androstenedione. Adrenal cortex function is regulated by pituitary adrenocorticotropin. Adrenal Glands: Anatomy: major source of androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens in women and prepubertal children
  • Some forms of AI may include androgen deficiency.
  • Exception is congenital adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation in children:
    • 21-hydroxylase deficiency 21-hydroxylase deficiency Congenital Adrenal Hyperplasia or 11-beta-hydroxylase deficiency causes disrupted steroid biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology; signals an increase in ACTH
    • Results in adrenal insufficiency but adrenal androgen excess 
  • DHEA DHEA A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (dhea) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens:
    • Weak androgenic activity
    • Precursor can be peripherally converted to more potent androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens (e.g., testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens) and estrogens (e.g., estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Noncontraceptive Estrogen and Progestins).
    • In postpubertal males, the testes Testes Gonadal Hormones are the main source of androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens.
• Mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids:
  • Regulation of renal sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia and water reabsorption 
  • Regulation of potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia excretion

Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease^[6,7]

Primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease:

• Manifestations emerge when > 90% of the adrenal cortex Adrenal Cortex The outer layer of the adrenal gland. It is derived from mesoderm and comprised of three zones (outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis) with each producing various steroids preferentially, such as aldosterone; hydrocortisone; dehydroepiandrosterone; and androstenedione. Adrenal cortex function is regulated by pituitary adrenocorticotropin. Adrenal Glands: Anatomy ( zona glomerulosa Zona Glomerulosa The narrow subcapsular outer zone of the adrenal cortex. This zone produces a series of enzymes that convert pregnenolone to aldosterone. The final steps involve three successive oxidations by cytochrome p-450 cyp11b2. Adrenal Glands: Anatomy, fasciculata, and reticularis) is destroyed.
• Hypocortisolism, hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism, and hypoandrogenism (men still produce androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens in testes Testes Gonadal Hormones) 
• Compensatory ↑ ACTH:
  • Leads to hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi
  • Both ACTH and ɑ-melanin-stimulating hormone are derived from pro-opiomelanocortin (POMC) → melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions stimulated

Secondary AI Secondary AI Deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion. Adrenal Insufficiency and Addison Disease:

• ↓ ACTH → hypocortisolism and hypoandrogenism
• Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia production preserved (as primary regulation is through the renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation–angiotensin system)
• No hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi, as ACTH is not increased

Tertiary AI Tertiary AI Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease:

• ↓ CRH → ↓ ACTH → hypocortisolism and hypoandrogenism
• Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia production preserved

Clinical Presentation

The signs and symptoms of AI depend on the rate at which it develops and the degree of loss of adrenal hormones Adrenal hormones There are 2 primary portions of the adrenal glands, the adrenal medulla and the adrenal cortex. The adrenal medulla is the inner portion of the gland, secreting epinephrine and, to a lesser degree, norepinephrine. The adrenal cortex is the outer portion of the gland and secretes mineralocorticoids, glucocorticoids, and androgens. Adrenal Hormones. Many symptoms are similar in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with different types of AI. Still, the clinical presentation varies depending on whether AI is acute ( adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison Disease) or chronic (primary, secondary, or tertiary).

Primary adrenal insufficiency Primary adrenal insufficiency An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease^[2,6,7]

Signs and symptoms of primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease relate to glucocorticoid, mineralocorticoid, and androgen deficiency.

• ↓ Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids:
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
  • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery/ anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa
  • Myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy/joint pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Abdominal pain Abdominal Pain Acute Abdomen/ diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension (including orthostatic hypotension Orthostatic hypotension A significant drop in blood pressure after assuming a standing position. Orthostatic hypotension is a finding, and defined as a 20-mm hg decrease in systolic pressure or a 10-mm hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing. Symptoms generally include dizziness, blurred vision, and syncope. Hypotension)
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia (due to ↑ antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia)
• ↓ Mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids:
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension (including orthostatic hypotension Orthostatic hypotension A significant drop in blood pressure after assuming a standing position. Orthostatic hypotension is a finding, and defined as a 20-mm hg decrease in systolic pressure or a 10-mm hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing. Symptoms generally include dizziness, blurred vision, and syncope. Hypotension)
  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
  • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
  • Salt craving
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
• ↓ Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens:
  • ↓ Axillary and pubic hair
  • Loss of libido Loss of libido Male Sexual Dysfunction 
  • Amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System in women 
  • Dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
• Hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi from ↑ ACTH

Secondary and tertiary adrenal insufficiency Tertiary adrenal insufficiency Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease^[2,4]

• Glucocorticoid + androgen deficiency → associated signs/symptoms similar to primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease
• Mineralocorticoid production preserved → associated signs/symptoms not present
• No hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi (ACTH not elevated)

Adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison Disease^[2,6,10,14]

Adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison Disease is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation ( hyperthyroidism Hyperthyroidism Hypersecretion of thyroid hormones from the thyroid gland. Elevated levels of thyroid hormones increase basal metabolic rate. Thyrotoxicosis and Hyperthyroidism).

Presentation:

• Hypovolemic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock (from reduced volume and mineralocorticoid deficiency)
• Can mimic acute abdomen Acute Abdomen Acute abdomen, which is in many cases a surgical emergency, is the sudden onset of abdominal pain that may be caused by inflammation, infection, perforation, ischemia, or obstruction. The location of the pain, its characteristics, and associated symptoms (e.g., jaundice) are important tools that help narrow the differential diagnosis. Acute Abdomen (abdominal tenderness, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever)
• Nonspecific symptoms:
  • Weakness
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
  • Anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa
• Confusion or decreased responsiveness progressing to coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma

Precipitating factors:

• Severe infection or other acute major stress in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with chronic primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease
• Abrupt withdrawal from supraphysiologic doses of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids used for other systemic diseases (e.g., asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma)
• Under-replacement of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids/ mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with primary or secondary AI Secondary AI Deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion. Adrenal Insufficiency and Addison Disease
• Acute adrenal destruction (e.g., hemorrhage)
• Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types infarction

Diagnosis

The diagnosis of AI is confirmed by laboratory testing results showing a morning (8 AM) serum cortisol Cortisol Glucocorticoids level of < 3 µg/dL. AI is virtually excluded if the cortisol Cortisol Glucocorticoids level is > 18 µg/dL, but patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with indeterminate results of 3–18 µg/dL require additional testing. All patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with acute AI should be evaluated for sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock, adrenal hemorrhage, and metastatic disease.

Initial tests for hypocortisolism

Morning serum cortisol Cortisol Glucocorticoids:^[2,6,7]

• Should be performed in the morning owing to diurnal variation Diurnal Variation Fever
• Cutoff value will depend on the assay.
• Limited diagnostic value:
  • May be measured at a physiologically low point in diurnal rhythm
  • Can be relatively normal in secondary AI Secondary AI Deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion. Adrenal Insufficiency and Addison Disease
• Very low cortisol Cortisol Glucocorticoids (e.g., ≤ 3 µg/dL or < 80 nmol/L): strongly suggests AI^[6]
• High cortisol Cortisol Glucocorticoids (e.g., > 18 µg/dL or > 430‒500 nmol/L): AI unlikely
• Further testing with the cosyntropin stimulation test is needed if the diagnosis is unclear.

ACTH levels:^[2,7]

• Obtain baseline plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products ACTH level simultaneously with morning cortisol Cortisol Glucocorticoids
• Interpretation:
  • ↑ ACTH (> 300 ng/L or > 2-fold the upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal; with low cortisol Cortisol Glucocorticoids): suggests primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease^[6]
  • ↓  Or normal ACTH (with low cortisol Cortisol Glucocorticoids): suggests secondary/ tertiary AI Tertiary AI Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease

Standard high-dose ACTH-stimulation test Acth-Stimulation Test Adrenal Insufficiency and Addison Disease:^[2,6,7,14]

• Procedure:
  • Obtain baseline cortisol Cortisol Glucocorticoids and ACTH.
  • 250 µg of IV or IM cosyntropin is administered (ACTH stimulation).
  • Measure serum cortisol Cortisol Glucocorticoids concentrations at 30 and 60 minutes.
• Interpreting results:
  • No rise in cortisol Cortisol Glucocorticoids → inappropriate adrenal response to ACTH:
    • With ↑ baseline ACTH → primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease
    • With ↓ baseline ACTH → long-standing secondary or tertiary AI Tertiary AI Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease
  • Rise in cortisol Cortisol Glucocorticoids → appropriate adrenal response to ACTH:
    • With ↓ baseline ACTH → secondary or tertiary AI Tertiary AI Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease
• Notes:
  • Newer monoclonal antibody immune assays or liquid chromatography– mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast spectrometry (LC-MS) assays are more specific; a stimulated cortisol Cortisol Glucocorticoids level of 14–15 µg/dL is considered normal. 
  • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cortisol Cortisol Glucocorticoids is protein-bound; falsely ↓ levels can be seen with significant hypoalbuminemia Hypoalbuminemia A condition in which albumin level in blood (serum albumin) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (albuminuria). Nephrotic Syndrome in Children.

Basal renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation, aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia, and electrolyte levels help in interpretation, especially in primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease:^[6,7]

• ↑ Renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation → primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease
• ↓ Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia levels → primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease
• Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes:
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia → more suggestive of primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
  • Nonanion gap metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis → more suggestive of primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease

Other laboratory findings^[2,6]

• Due to glucocorticoid deficiency:
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • Thrombocytosis
  • Eosinophilia Eosinophilia Abnormal increase of eosinophils in the blood, tissues or organs. Autosomal Dominant Hyperimmunoglobulin E Syndrome
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia (more common in children)
• Due to mineralocorticoid deficiency:
  • ↑ Creatinine (from volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration)
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia 
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia

Additional tests for hypothalamic– pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types–adrenal function^[7]

The following tests may be performed when initial testing is indeterminate. However, they are typically not required and should be done only in conjunction with specialist consultation.

• Metyrapone Metyrapone An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of Cushing syndrome. Adrenal Insufficiency and Addison Disease test:
  • Metyrapone Metyrapone An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of Cushing syndrome. Adrenal Insufficiency and Addison Disease blocks conversion of 11-deoxycortisol to cortisol Cortisol Glucocorticoids.
  • Oral metyrapone Metyrapone An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of Cushing syndrome. Adrenal Insufficiency and Addison Disease given, followed by obtaining 11-deoxycortisol and cortisol Cortisol Glucocorticoids after 24 hours
  • Primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease: ↑ ACTH but no increase in 11-deoxycortisol and cortisol Cortisol Glucocorticoids 
  • Secondary/ tertiary AI Tertiary AI Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease: low ACTH, no increase in 11-deoxycortisol and cortisol Cortisol Glucocorticoids 
• Insulin-induced hypoglycemia test Insulin-Induced Hypoglycemia Test Adrenal Insufficiency and Addison Disease:
  • Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin causes ↓ glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance, which in turn, triggers cortisol Cortisol Glucocorticoids secretion Secretion Coagulation Studies in normal circumstances.
  • Inject insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin.
  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance, ACTH, and cortisol Cortisol Glucocorticoids are measured in intervals.
  • Primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease: ↑ ACTH without increase in cortisol Cortisol Glucocorticoids despite hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Secondary AI Secondary AI Deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion. Adrenal Insufficiency and Addison Disease: Inadequate ↑ in cortisol Cortisol Glucocorticoids and ACTH at the onset of hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia 
  • Contraindicated in cardiovascular disease and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
• Corticotropin-releasing hormone Corticotropin-releasing hormone A peptide of about 41 amino acids that stimulates the release of adrenocorticotropic hormone. Crh is synthesized by neurons in the paraventricular nucleus of the hypothalamus. After being released into the pituitary portal circulation, crh stimulates the release of acth from the pituitary gland. Crh can also be synthesized in other tissues, such as placenta; adrenal medulla; and testis. Hypothalamic and Pituitary Hormones test differentiates secondary from tertiary adrenal insufficiency Tertiary adrenal insufficiency Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease.
  • Secondary AI Secondary AI Deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion. Adrenal Insufficiency and Addison Disease: no ACTH response
  • Tertiary AI Tertiary AI Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease: ↑ ACTH response
  • Does not make a difference in therapy

Diagnosing the etiology^[6]

In suspected primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease:

• Review medications (rule out drug-induced AI).
• Adrenocortical antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions or antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions against 21-hydroxylase:
  • Autoimmune adrenalitis
  • Autoimmune polyendocrine syndrome (proceed with other tests for hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism, diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy disease)
• Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products very-long-chain fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (VLCFAs):
  • In male patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with isolated Addison disease and negative autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques 
  • Elevated in adrenoleukodystrophy ( genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies required)
• In children in whom AI presents in infancy or childhood:
  • Serum 17-hydroxyprogesterone (17-OHP)
  • Routine newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn screening Screening Preoperative Care
• CT of the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands: Anatomy:
  • Tuberculous adrenalitis: spotty calcifications late in the disease 
  • May detect malignancy Malignancy Hemothorax such as lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum and adrenal metastases
  • Adrenal infiltration ( sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis, amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis, hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis) 
  • Adrenal hemorrhage

In suspected secondary/ tertiary AI Tertiary AI Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease:

• Workup of hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism (e.g., thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones (TSH))
• MRI of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus and pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland

Management

Optimal dosing for glucocorticoid replacement therapy for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with primary and secondary AI Secondary AI Deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion. Adrenal Insufficiency and Addison Disease is not well agreed on. Still, insufficient replacement can result in adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison Disease, and chronic excess doses may cause cardiovascular disease and increased mortality Mortality All deaths reported in a given population. Measures of Health Status.^[10] Specialty referral (e.g., endocrinology) is indicated in most cases. 

The following information was gleaned from US, UK, and European literature and guidelines. 

Adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison Disease

Background:^[6,12]

• Acute AI is a life-threatening emergency!
• Clinical suspicion of adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison Disease requires immediate therapy even before diagnosis is established.

Initial management:^[6,10,12,14]

• Stabilize airway Airway ABCDE Assessment and breathing
• Obtain IV access
• Cardiac monitoring
• Draw blood for:
  • CBC
  • Metabolic panel
  • Infection screening Screening Preoperative Care (e.g., blood cultures)
  • Serum cortisol Cortisol Glucocorticoids
  • ACTH
  • Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia
  • Renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation
• IV fluid resuscitation Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome:
  • Give rapid infusion of 0.9% saline (start with 1 L within 1 hour)
  • Add 50 g/L of dextrose Dextrose Intravenous Fluids (5%) to fluids if hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia is present.
  • Amount and rate of fluids should be guided by clinical course and urine output.
  • Avoid hypotonic Hypotonic Solutions that have a lesser osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. Renal Sodium and Water Regulation solution → can worsen hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
• IV hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants (has mineralocorticoid activity):
  • 100 mg IV every 6–8 hours (IM administration possible if IV access not available)
  • Can also do continuous infusion
  • Should see clinical improvement within 4–6 hours^[6]
  • Alternative: prednisolone Prednisolone A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. Immunosuppressants
• If the diagnosis of AI is yet not established:
  • May consider a single dose of dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics 10 mg IV (instead of hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants) → does not interfere with test results
  • Start rapid infusion of IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids as above.
  • Perform cosyntropin stimulation test (any time of day), then start IV hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants
• Treat hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, as needed

Once stabilized:^[6,12–14]

• May slow IV fluid rate, maintain for 24–48 hours
• Search for underlying condition and treat accordingly.
• Hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants adjustment:
  • After 24 hours, can reduce to 50 mg IV every 6 hours
  • Taper IV dose over the next few days
  • Eventual dose:
    • 10 mg in the AM
    • 5 mg at lunch
    • 5–10 mg in afternoon
  • Adjust to the lowest dose that provides symptom relief
• Once IV saline is discontinued and daily hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants dose is < 50 mg/day → fludrocortisone Fludrocortisone A synthetic mineralocorticoid with anti-inflammatory activity. Mineralocorticoids should be started for primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease
  • Dose: 0.1 mg daily
  • Adjust dose (usual range, 0.05–0.2 mg) as needed to maintain:
    • Normal blood pressure supine and standing
    • Normal potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia level
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should wear a medical identification Identification Defense Mechanisms tag or bracelet.

Maintenance therapy^[11–13]

• Start when IV hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants dose has been decreased to < 100 mg.
• Cortisol Cortisol Glucocorticoids replacement:
  • Prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants 5 mg orally daily in the morning
  • Adjust to the lowest dose that provides symptom relief (usually 4–7.5 mg daily).
  • Alternative: hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants 10 mg orally in the morning and 5 mg in the afternoon
  • Higher doses may be needed concomitantly with drugs that accelerate glucocorticoid metabolism.
• Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease also require aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia replacement:
  • Fludrocortisone Fludrocortisone A synthetic mineralocorticoid with anti-inflammatory activity. Mineralocorticoids 0.1 mg orally daily
  • Adjust dose (usual range, 0.05–0.2 mg) as needed to maintain:
    • Normal blood pressure supine and standing
    • Normal potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia level
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should wear a medical identification Identification Defense Mechanisms tag or bracelet.

Chronic adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease

Primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease:^[6,10,12,13]

• Glucocorticoid replacement:
  • Oral hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants (in 2–3 divided doses to mimic diurnal rhythm)
  • Alternatives: prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants/ prednisolone Prednisolone A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. Immunosuppressants
  • Situations of stress require escalated doses (e.g., surgery, infection).
  • Monitor:
    • Body weight
    • Symptoms
    • Blood pressure
    • Energy
• Mineralocorticoid replacement:
  • Prevention of hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia, loss of fluids and sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia
  • Fludrocortisone Fludrocortisone A synthetic mineralocorticoid with anti-inflammatory activity. Mineralocorticoids
    • Given daily
    • Dose increased in warm weather due to salt loss in perspiration
    • Monitor BP, electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes, renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation → adjust dose as needed
• Adrenal androgen replacement:
  • In women, the adrenal gland is the main source of androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens.
  • DHEA DHEA A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (dhea) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens may improve loss of libido Loss of libido Male Sexual Dysfunction and/or low energy levels in women.
  • Discontinue if no benefit after 6-month trial
• Underlying causes must be treated (e.g., resection of tumors, antibiotics for infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease).

Secondary and tertiary AI Tertiary AI Deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH). Adrenal Insufficiency and Addison Disease:^[6,12,13]

• Glucocorticoid replacement:
  • Similar to primary AI Primary AI An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. 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. Adrenal Insufficiency and Addison Disease
  • Options:
    • Hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants
    • Prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants/ prednisolone Prednisolone A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. Immunosuppressants
    • Dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics
  • ACTH not used for monitoring and titration of glucocorticoid dose
• Mineralocorticoid replacement rarely required
• Replacement of other anterior pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types, if indicated (e.g., thyroxine Thyroxine The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroid Hormones, growth hormone) → may affect glucocorticoid dosing

Follow-up:^[6,10]

• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should be followed closely by endocrinology specialist.
• Follow-up should be scheduled annually, at a minimum.

Illness or surgery^[6,10,12,13]

• Minor illness:
  • Double the usual dose of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids for 2–3 days, then resume the maintenance dose Maintenance Dose Dosage Calculation
  • No change to mineralocorticoid dosing needed
• Illness with vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia:
  • Give IV glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids and IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids.
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may be given a 4-mg vial of dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics and taught to self-administer IM if medical care Medical care Conflict of Interest is not immediately available.
• Severe illness:
  • Hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants 100 mg for 1 dose
  • Followed by either:
    • 50 mg IV/IM every 6–8 hours
    • Continuous infusion (200 mg in 24 hours)
  • Taper with recovery
• Surgery:
  • Hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants 50–100 mg IV preoperatively
  • If major surgery with anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts, follow up with either:
    • Continuous infusion (200 mg in 24 hours)
    • 50 mg IV every 6 hours
  • Taper to usual maintenance therapy over 2–3 days if the patient is tolerating oral intake.
• Critical illness–related corticosteroid insufficiency (CIRCI) with septic shock Septic shock Sepsis associated with hypotension or hypoperfusion despite adequate fluid resuscitation. Perfusion abnormalities may include, but are not limited to lactic acidosis; oliguria; or acute alteration in mental status. Sepsis and Septic Shock:
  • Consider if:
    • Not responsive to fluids 
    • Moderate- to high-dose vasopressor Vasopressor Acute Cholangitis therapy required
  • Start hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants IV (< 400 mg/day) for ≥ 3 days.

Clinical Relevance

• Hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism: pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types hormone deficiency, resulting from a disease of the pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland (commonly tumors), but may arise from hypothalamic dysfunction: The anterior lobe Anterior lobe Cerebellum: Anatomy produces growth hormone, follicle-stimulating hormone, luteinizing hormone, TSH, ACTH, and prolactin Prolactin A lactogenic hormone secreted by the adenohypophysis. It is a polypeptide of approximately 23 kd. Besides its major action on lactation, in some species prolactin exerts effects on reproduction, maternal behavior, fat metabolism, immunomodulation and osmoregulation. Breasts: Anatomy. Loss of antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia and oxytocin occurs in posterior lobe Posterior lobe Cerebellum: Anatomy damage. Diagnosis is via hormone levels, provocation tests, and brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification imaging. Treatment is hormonal replacement.
• Syndrome of inappropriate antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia ( SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)): disorder of impaired water excretion due to the inability to suppress the secretion Secretion Coagulation Studies of ADH/vasopressin: This disorder can be due to disease, medications, ectopic secretion Secretion Coagulation Studies by cancer, or hereditary causes (nephrogenic SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)). SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) also occurs in cortisol Cortisol Glucocorticoids deficiency. Loss of cortisol Cortisol Glucocorticoids results in absence of negative feedback Negative feedback Hypothalamic and Pituitary Hormones on ADH secretion Secretion Coagulation Studies, increasing ADH. Low cortisol Cortisol Glucocorticoids also triggers increased CRH, an ADH secretagogue. Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia and hypoosmolality are findings. Management depends on the underlying etiology.
• Congenital adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation ( CAH CAH Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of cah is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia):  inherited autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance disease characterized by enzyme deficiency that impairs adrenal hormone production, which results in the overproduction of the hormone precursor. 95% of CAH CAH Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of cah is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia is due to the absence of the enzyme 21-hydroxylase, leading to inability to produce cortisol Cortisol Glucocorticoids, and often accompanied by salt wasting. Females exhibit atypical genitalia from virilizing effects (increased androgen from hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation). Neonatal screening Screening Preoperative Care is by measurement of 17-OHP (elevated hydroxyprogesterone). Management involves glucocorticoid and mineralocorticoid therapy. 
• Adrenoleukodystrophy: a rare X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) genetic disorder caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the ABCD1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics and associated with buildup of VLCFAs (very-long-chain fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance): This buildup causes destruction of the myelin sheath of nerves, adrenal cortex Adrenal Cortex The outer layer of the adrenal gland. It is derived from mesoderm and comprised of three zones (outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis) with each producing various steroids preferentially, such as aldosterone; hydrocortisone; dehydroepiandrosterone; and androstenedione. Adrenal cortex function is regulated by pituitary adrenocorticotropin. Adrenal Glands: Anatomy, and testes Testes Gonadal Hormones. Children have learning disabilities Learning disabilities Conditions characterized by a significant discrepancy between an individual’s perceived level of intellect and their ability to acquire new language and other cognitive skills. These may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. DiGeorge Syndrome, behavior problems, and quadriparesis. Adrenoleukodystrophy can present in adulthood, with young adults having spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy and gonadal dysfunction. Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease is one of the manifestations. Diagnosis is via a VLCFA panel. Treatment options include glucocorticoid therapy, hematopoietic–cell transplantation, and supportive interventions.