Secondary adrenal insufficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones, primarily cortisol, but may also include impaired aldosterone production (a mineralocorticoid) which regulates electrolytes mainly sodium and potassium along side with water retention.^[1][2] Craving for salt or salty foods due to the urinary losses of sodium is common.^[3]

Adrenal insufficiency can also occur when the hypothalamus or the pituitary gland, both located at the base of the skull, does not make adequate amounts of the hormones that assist in regulating adrenal function.^[1][4][5] This is called secondary adrenal insufficiency and is caused by lack of production of ACTH in the pituitary or lack of CRH in the hypothalamus.^[6] Accordingly, it is classified in to 2 types, primary adrenal insufficiency and secondary adrenal insufficiency. It must be differentiated from other diseases that may cause hypotension, fatigue, and skin pigmentation. The most potent risk factor in the development of secondary adrenal insufficiency is infections, such as Tuberculosis. Its common complications include hypoglycemia, adrenal crisis,hypovolemic shock and cardiac arrest. Prognosis is generally good in patients with secondary adrenal insufficiency as long as they are on life-time hormonal therapy. The most common symptoms of secondary adrenal insufficiency include Chronic fatigue, weight loss, and visual field defects. The main stay of treatment for secondary adrenal insufficiency is treating the underlying cause. For symptomatic cases, hydrocortisone should be administered. The long-term treatment goal is to maintain normal blood pressure, blood glucose, fluid volume, and a sense of well-being in the patient.

Suprarenal glands were discovered by Eustachius in 1563 and were named as Glandulae renis incumbentes. 35th USA President John F. Kennedy had primary Adrenal insufficiency (Addison’s disease).

Adrenal insufficiency is classified into 2 types based on the level of impairment, primary adrenal insufficiency and secondary adrenal insufficiency.

Secondary adrenal insufficiency is caused by the processes occurring outside adrenal glands: pituitary causes, drugs, genetic causes.These disease processes causes the decreased production of adrenocorticotrophic hormone (ACTH).

Secondary adrenal insufficiency is caused mainly by 4 categories, hypopituitarism, drugs, genetic and other causes. Life-threatening causes include acute withdrawal of steroids, adrenal hemorrhage, Waterhouse-Friderichson syndrome, anti-coagulation and gastroenteritis which causes adrenal crisis. The common causes include chronic steroid therapy and its withdrawal, opiates, causes of pan-hypopituitarism and the less common causes are genetic causes which include combined pituitary hormone deficiency (CPHD), proopiomelanocortin deficiency POMC and isolated ACTH deficiency.

Secondary adrenal insufficiency must be differentiated from primary adrenal insufficiency, acute adrenal insufficiency/adrenal crisis, adrenal hemorrhage, congenital adrenal hyperplasia and salt losing nephropathy based on clinical features, such as fatigue and weight loss and laboratory findings.

The prevalence of secondary adrenal insufficiency is approximately 15-28 per 100,000 individuals worldwide more common than Addison disease. The incidence increases with age; the median age at diagnosis is 60 years. There is no racial predilection.Women are more commonly affected by secondary adrenal insufficiency than male.

The most potent risk factor in the development of secondary adrenal insufficiency is infections, such as Tuberculosis. Other risk factors include genetic defects of adrenal gland, diabetes, and Vitiligo.

There is insufficient evidence to recommend routine screening for secondary adrenal insufficiency.

If left untreated, secondary adrenal insufficiency can be life-threatening. Any stressful event or illness can cause a sudden worsening of symptoms, which can lead to severe dehydration and fatally low blood pressure and eventually death from adrenal crisis.Common complications include hypoglycemia, adrenal crisis,hypovolemic shock and cardiac arrest. Prognosis is generally good in patients with secondary adrenal insufficiency as long as they are on life-time hormonal therapy. Patients with secondary adrenal insufficiency must be closely monitored for compliance with medications as acute cases can be life-threating and the mortality rates can go up to 95% in acute crisis.

The most common symptoms of secondary adrenal insufficiency include chronic fatigue, weight loss, and visual field defects.

Patients with secondary adrenal insufficiency usually appear weak or cushingoid (if the cause is glucocorticoid withdrawal). Physical examination of patients with secondary adrenal insufficiency is usually remarkable for cushingoid features like muscle weakness, buffalo hump. Hypotension may or may not be present. The absence of hyperpigmentation is the hallmark and a distinguishing feature of secondary adrenal insufficiency. Also, the presence of visual field defects like bitemporal hemianopsia indicates a pituitary tumor.

Laboratory findings consistent with the diagnosis of adrenal insufficiency may include eosinophilia,lymphocytosis,normocytic anemia,hyponatremia , mild hypercalcemia, and azotemia. Secondary adrenal insufficiency may be confirmed by dynamic tests such as insulin tolerance test and corticotropin stimulation test (standard and low dose). Adrenal function can be assessed by measuring basal ACTH secretion and ACTH reserve (via Metyrapone stimulation test).

There are no ECG findings associated with secondary adrenal insufficiency.

There are no x-ray findings associated with secondary adrenal insufficiency.

CT findings suggestive of chronic adrenal insufficiency may include small and atrophic adrenal gland. CT head findings suggestive of pituitary disorder leading to adrenal insufficiency may include hemorrhage in case of pituitary apoplexy or a mass suggestive of pituitary adenoma or craniopharyngioma.

MRI is the diagnostic imaging modality used in secondary adrenal insufficiency to assess hypothalamic pituitary adrenal axis. MRI findings suggestive of pituitary abnormality may include a mass suggesting a tumor or empty sella leading to hypopituitarism.

There are no ultrasound findings associated with secondary adrenal insufficiency

There are no other imaging findings associated with secondary adrenal insufficiency.

There are no other diagnostic studies associated with secondary adrenal insufficiency.

The mainstay of treatment for secondary adrenal insufficiency is treating the underlying cause. For symptomatic cases, hydrocortisone should be administered. The long-term treatment goal is to maintain normal blood pressure, blood glucose, fluid volume, and a sense of well-being in the patient.

The mainstay of treatment for secondary adrenal insufficiency is medical therapy. Surgery is usually reserved for tumor of the pituitary which is causing secondary adrenal insufficiency due to mass effect and is resistant to medical therapy.

There are no established measures for the primary prevention of secondary adrenal insufficiency. However, the risk can be minimized by preventing hypopituitarism by good obstetric care and minimizing radiation exposure as hypopituitarism is the main cause of secondary adrenal insufficiency. The other effective measures are tapering of steroids and avoidance of the long-term use of opioids.

Effective measures for the secondary prevention of secondary adrenal insufficiency include patient and family members education about risks of hormone replacement therapy and dose adjustments during periods of acute illnesses.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

Suprarenal glands were discovered by Eustachius in 1563 and were named as Glandulae renis incumbentes. 35th USA President John F. Kennedy had primary Adrenal insufficiency (Addison’s disease).

• Suprarenal glands were discovered by Eustachius in 1563 and were named as Glandulae renis incumbentes.^[1]

• Primary adrenal insufficiency was first discovered by Thomas Addison, an English physician, and scientist, when he described adrenocortical atrophy in 1849 on the autopsy of the adrenal glands of patients, some of which had vitiligo.^[2]

• In 1926, Schmidt was the first to discover the association between adrenalitis and thyroiditis, called Schmidt’s syndrome, which was expanded by Carpenter in 1964 to include type 1 diabetes mellitus.

• In 1956, Whittaker found an association between hypo-adrenocortolism, hypothyroidism, and candidiasis.^[3]

• In 1997, AIRE gene mutations were first implicated in the pathogenesis of APS (autoimmune polyglandular syndrome).

• 35th USA President John F. Kennedy had primary adrenal insufficiency (Addison’s disease).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

Adrenal insufficiency is classified into 2 types based on the level of impairment, primary adrenal insufficiency and secondary adrenal insufficiency. Secondary adrenal insufficiency may be further classified based on the causes into three types, such as hypopituitary causes, medication causes, and genetic causes.

Adrenal insufficiency is classified into 2 types based on the level of impairment.

Primary adrenal insufficiency

• Primary adrenal insufficiency is due to impairment of the adrenal gland, 80% due to an autoimmune disease called Addison’s disease or autoimmune adrenalitis. Also, the other cause includes autoimmune polyendocrine syndrome type 1 and type 2.

Secondary adrenal insufficiency

• Secondary adrenal insufficiency is caused by impairment of the pituitary gland or hypothalamus. The principal causes include pituitary adenoma (which can suppress production of adrenocorticotropic hormone (ACTH) and lead to adrenal deficiency unless the endogenous hormones are replaced); and Sheehan’s syndrome, which is associated with impairment of only the pituitary gland.
• Secondary adrenal insufficiency may be further classified based on the causes into three types:
  • Hypopituitary causes
  • Medication induced
  • Genetics

Adrenal Insufficiency

Primary adrenal insufficiency

Secondary adrenal insufficiency

•Addison’s disease •Autoimmune adrenalitis •Autoimmune polyendocrine syndrome type 1 and type 2 •Idiopathic

Hypopituitarism •Tumors-Craniopharyngioma •Tuberculosis[1][2] •Histoplasmosis [3] •Pituitary infarction-Sheehan’s syndrome, pituitary apoplexy •Removal of pituitary due to metastasis •Lymphycytic hypophysitis •Head trauma •Intracranial artery aneurysms Drugs •Chronic high dose steroid •Opiates- Codeine, Morphine Genetic causes •Isolated ACTH deficiency •POMC deficiency •Combined Pituitary Hormone Deficiency (CPHD)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

Secondary adrenal insufficiency is caused by the processes occurring outside adrenal glands: pituitary causes, drugs, genetic causes.These disease processes causes the decreased production of adrenocorticotrophic hormone (ACTH).

• Hypothalamus produces corticotropin releasing hormone (CRH) that stimulates pituitary gland‘s corticotrophs to release adrenocorticotrophic hormone ( ACTH).
• Anterior pituitary gland‘s corticotroph cells produce ACTH that in turn stimulates adrenal cortex‘s zona glomerulosa to produce cortisol.
• Cortisol is produced by zona glomerulosa of the adrenal gland and provides feedback to pituitary and hypothalamus.

• Secondary adrenal insufficiency is caused by the processes occurring outside adrenal glands: pituitary causes, drugs, and genetic causes.
• These disease processes causes the decreased production of adrenocorticotrophic hormone (ACTH).
• Chronic steroid therapy causes suppression of hypothalamic pituitary adrenal axis (HPA) axis.
• In some cases of adrenal insufficiency, hyponatremia is seen due to an abnormal increase in antidiuretic hormone(ADH) which in turn caused due to deficiency of cortisol due to decreased excretion of free water. The feedback loop causes secretion of corticotropin-releasing hormone (CRH), again an ADH secretagogue. There is a negative feedback on CRH and ACTH by cortisol. In adrenal insufficiency, this effect is removed and cortisol inhibits ADH excretion directly showing the reciprocal relation of ADH increase when cortisol is low. ADH inappropriate secretion leads to more water absorption leading to hyponatremia.^[1]

• Secondary adrenal insufficiency is also caused by genetic disorders.
  • Combined pituitary hormone deficiency (CPHD)
  • Proopiomelanocortin deficiency (POMC)^[2]

• POMC deficiency is transmitted in autosomal recessive transmission pattern.
• Genes involved in the pathogenesis of POMC deficiency include POMC gene.
• Genes involved in the pathogenesis of CPHD include PROP-1 where ACTH deficiency occurs in the end after GH, Prolactin, TSH, and LH/FSH deficiencies. Other genes in CPHD include HESX1, LHX3, LHX4 and SOX3.

• Hypopituitarism
• Adrenal crisis
• Adrenal hemorrhage
• Hyponatremia

• The gross pathology features are dependent on the cause. For the gross pathology, when secondary adrenal insufficiency is caused by hypopituitarism, click here.

• The microscopic pathology features are dependent on the cause. For the microscopic pathology when the cause is hypopituitarism, click here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

Secondary adrenal insufficiency is caused mainly by four categories, hypopituitarism, drugs, genetic and other causes. Life-threatening causes include acute withdrawal of steroids, adrenal hemorrhage, Waterhouse-Friderichson syndrome, anticoagulation and gastroenteritis which causes adrenal crisis. The common causes include chronic steroid therapy and its withdrawal, opiates, causes of panhypopituitarism and the less common causes are genetic causes which include combined pituitary hormone deficiency (CPHD), proopiomelanocortin deficiency POMC and isolated ACTH deficiency.

Life-threatening causes of secondary adrenal insufficiency include causes of acute adrenal crisis/insufficiency:

• Acute withdrawal of steroids.
• Traumatic hypopituitarism.^[1]
• Adrenal hemorrhage
  • Waterhouse-Friderichson syndrome
  • Anticoagulation.
• Gastroenteritis.^[2]

Secondary adrenal insufficiency may be caused by:

• Drugs
  • Chronic steroid therapy and its withdrawal
  • Opiates
  • Etomidate
  • Antifungals- ketoconazole^[3]
• Pituitary causes:
  • Infections- tuberculosis
  • Pituitary infarction
    • Pituitary apoplexy
    • Sheehan’s syndrome
  • Pituitary removal
  • Pituitary irradiation

Less common causes of secondary adrenal insufficiency include:

• Pituitary causes
  • Lymphocytic hypophysitis
  • Tumors- craniopharyngioma, metastasis,

• Genetic causes:
  • Combined pituitary hormone deficiency (CPHD)
  • Proopiomelanocortin deficiency (POMC)
  • Isolated ACTH deficiency

Cardiovascular	Arteritis, Hypotension, Hemorrhage, Infarction
Chemical / poisoning	No underlying causes
Dermatologic	POEMS syndrome
Drug Side Effect	Aminoglutethimide, Ciclesonide, Cidofovir, Corticosteroid withdrawal, Dexamethasone, Flunisolide, Pembrolizumab,prednisolone, Trilostane
Ear Nose Throat	No underlying causes
Endocrine	Allgrove syndrome, Achalasia-addisonian syndrome, Adrenal aplasia / adrenal hypoplasia, Adrenal metastases, After surgery of cortisol-secreting tumor, Autoimmune polyendocrine syndrome type 2, Bilateral adrenalectomy , Congenital adrenal hyperplasia, Glucocorticoid deficiency 1, IMAGE syndrome, POEMS syndrome, X-linked adrenal hypoplasia congenita
Environmental	No underlying causes
Gastroenterologic	Allgrove syndrome, Achalasia-addisonian syndrome, Hemochromatosis
Genetic	Congenital adrenal hyperplasia, Cytochrome P450 oxidoreductase deficiency, Glycerol kinase deficiency, Hereditary ACTH resistance, IMAGE syndrome, X-linked adrenal hypoplasia congenita, Combined pituitary hormone deficiency (CPHD), Proopiomelanocortin deficiency (POMC), Isolated ACTH deficiency
Hematologic	Anticoagulation, Coagulopathy , Embolus, Leukemia, Lymphoma , Thrombosis
Iatrogenic	Iatrogenic, Radiation therapy, Chronic steroid therapy
Infectious Disease	AIDS, Blastomycosis, CMV, Coccidiomycosis, Cryptococcosis, Histoplasmosis , Mycobacterium avium intracellulaire (MAI), Sepsis, Syphilis, Toxoplasmosis, Tuberculosis, Waterhouse-Friderichson syndrome
Musculoskeletal / Ortho	IMAGE syndrome
Neurologic	Adrenoleukodystrophy, Coma, Craniopharyngioma, Panhypopituitarism, POEMS syndrome
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	Craniopharyngioma, Kaposi’s sarcoma, Leukemia, Lymphoma , pituitary metastasis
Ophthalmologic	No underlying causes
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	Sarcoidosis,
Renal / Electrolyte	Uremia, Waterhouse-Friderichson syndrome
Rheum / Immune / Allergy	Autoimmune, Autoimmune polyendocrine syndrome type 2, Sarcoidosis
Sexual	No underlying causes
Trauma	Trauma
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	Amyloidosis, Idiopathic, Iatrogenic, Radiation therapy, Surgery, Surgical removal of pituitary, Surgical removal of hypothalamus

Achalasia-addisonian syndrome[4] Adrenal aplasia / Adrenal hypoplasia Adrenal metastases Adrenoleukodystrophy[5] After surgery of cortisol-secreting tumor AIDS[6][7] Allgrove syndrome[4] Aminoglutethimide Amyloidosis Anticoagulation Arteritis Autoimmune Autoimmune polyendocrine syndrome type 2[8] Bilateral adrenalectomy Blastomycosis[9] CMV[10] Coagulopathy Coccidiomycosis Coma Combined pituitary hormone deficiency (CPHD) Congenital adrenal hyperplasia Corticosteroid withdrawal Craniopharyngioma[11] Cryptococcosis[12] Cytochrome P450 oxidoreductase deficiency Embolus Flunisolide Glucocorticoid deficiency 1[13] Glycerol kinase deficiency[14] Hemochromatosis[15]

Hemorrhage Hereditary ACTH resistance Histoplasmosis Hypotension Iatrogenic Idiopathic IMAGE syndrome[16] Infarction Isolated ACTH deficiency Kaposi’s sarcoma Leukemia Lymphoma Metastasis Mycobacterium avium intracellulaire (MAI)[17] Panhypopituitarism POEMS syndrome[18] Proopiomelanocortin deficiency (POMC) Radiation therapy Sarcoidosis[19] Sepsis Surgery Surgical removal of hypothalamus Surgical removal of pituitary Syphilis Thrombosis Toxoplasmosis Trauma Trilostane Tuberculosis Uremia Waterhouse-Friderichson syndrome X-linked adrenal hypoplasia congenita

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

Secondary adrenal insufficiency must be differentiated from primary adrenal insufficiency, acute adrenal insufficiency/adrenal crisis, adrenal hemorrhage, congenital adrenal hyperplasia and salt losing nephropathy based on clinical features, such as fatigue and weight loss and laboratory findings.

Secondary adrenal insufficiency must be differentiated from other diseases that may cause hypotension, fatigue, and skin pigmentation.

Acute/ Chronic	Disease	Clinical history/findings							Causes	Laboratory findings				Medical therapy
		Hypotension	Skin pigmentation/ findings	Fatigue	Anorexia/ weightloss	Abdominal pain	Muscle weakness	Other history findings		Hypo natremia	Cortisol levels	Gold Standard	Other
	Differentiating amongst adrenal insufficiencies
Chronic	Primary adrenal insufficiency/ Addison’s disease	+	+	+	+	+	+	Nausea and Vomiting Hypoglycemia	Autoimmune/idiopathic Infections- Tuberculosis[1][2], histoplasmosis[3][4]	+	Low	Cosyntropin/ ACTH stimulation test	Hyperkalemia	Hydrocortisone -15 to 25 mg PO q daily in 2 to 3 divided doses Fludrocortisone – 0.1 to 0.2 mg PO q daily
Chronic	Secondary adrenal insufficiency	±	–	+	+	–	±	Hypoglycemia (more than primary adrenal insufficiency) Signs of pituitary tumor- headache, visual field defects (bitemporal hemianopsia)	Hypopituitarism– Tumors, infections, hemorrhage/trauma Drugs- Chronic steroid therapy and its withdrawal, opiates[5] Genetic– Combined pituitary hormone deficiency (CPHD), POMC (proopiomelanocortin) gene deficiency	–	Normal	Cosyntropin/ ACTH stimulation test	CT scan/ MRI scan showing pituitary causes	Hydrocortisone -15 to 25 mg PO daily in 2 to 3 divided doses
Acute	Acute adrenal insufficiency/ Acute adrenal crisis	++	±	+	+	+	±	Signs of shock Altered mental status/ Loss of consciousness/ Coma Fever Nausea/ vomiting	Infection Trauma Surgery Anesthesia (etomidate)	+	“Normal to Low	“Cosyntropin/ ACTH stimulation test	ECG (electrocardiogram) CBC (complete blood count) BUN (blood urea nitrogen) Creatinine	I/V 0.9% saline 1-3 liters within 12-24 hours I/V Dexamethasone 4 mg bolus, or, I/V hydrocortisone 50 mg bolus Fludrocortisone – 0.1 to 0.2 mg PO q daily after initial stabilization
Differentiating Adrenal Insufficiency from other diseases
	Adrenal hemorrhage/ Waterhouse Friderichsen syndrome	Orthostatic	±	+	±	+	–	Fever Tachycardia Dizziness Nausea/ vomiting Diarrhea	Infection Sepsis- pneumonia Waterhouse Friderichsen syndrome- meningococcemia Cardiac- Congestive heart failure (CHF), myocardial infarction Gastrointestinal- Acute pancreatitis, cirrhosis Bleeding situations- Spontaneous abortions, thrombocytopenia, anticoagulants use, surgery, heparin-induced thrombocytopenia Trauma Thrombotic phenomenon- pulmonary embolus, deep venous thrombosis, antiphospholipid antibody syndrome Tumors- Adrenal adenomas, pheochromocytoma	+	Normal to low	Cosyntropin/ ACTH stimulation test	CBC (Complete blood count) CT scan	Stabilize the patient Treat the underlying cause
	Congenital adrenal hyperplasia (CAH)	Normal to hypertension	± (can be indicator of Uncontrolled CAH)[6]	–	–	–	–	Female- Ambiguous genitalia/ virilization, infertility Male- Normal or enlarged phallus Short stature	21-hydroxylase deficiency 17α hydroxylase deficiency 11 β hydroxylase deficiency	±	Low	Cosyntropin/ ACTH stimulation test	Serum 17-hydroxyprogesterone Hyperkalemia	Hydrocortisone -15 to 25 mg PO daily in 2 to 3 divided doses Fludrocortisone – 0.1 to 0.2 mg PO q daily
	Syndrome of inappropriate antidiuretic hormone (SIADH)	–	–	–	–	–	–	Nausea/vomiting Cramps Depressed mood Irritability Confusion Hallucinations Seizures, stupor or coma	Head trauma-subarachnoid hemorrhage Tumors- metastasis Infections- Brain abscess Drugs- chlorpropamide, cyclophosphamide, carbamazepine, selective serotonin reuptake inhibitors, methylenedioxymethamphetamine (MDMA, commonly called Ecstasy)	+	Normal	Water deprivation test	Decreased osmolality Euvolemia Sodium in urine typically >20 mEq/	Mild- Fluid restriction Moderate- Loop diuretics Severe Hypertonic (3%) saline
	Salt-depletion nephritis/ Salt losing nephropathy	+	–	–	–	+ Flank pain	–	Fever Dysuria Pyuria Oliguria	Chronic renal failure Bartter syndrome[7] Gitelman syndrome Drugs- Tacrolimus[8]	++[9]	High	Genetic study	<15:1 BUN:CR	Fludrocortisone – 0.05 to 0.2 mg PO q daily
	Anorexia nervosa	+	–	+	+	–	+	Distorted body image Hypoglycemia Amenorrhoea/ oligomenorrhoea Osteoporosis Refeeding syndrome	Genetic Hormonal- Low dopamine and serotonin Psychological	–	High	Psychiatric condition	–	Nutritional replacement Psychotherapy- e.g. Cognitive behavioral therapy For refeeding syndrome-hospitalization and replacements of potassium, phosphate and magnesium

Adrenal insufficiency must be differentiated from other causes of headache, polyuria and polydypsia.

Disease	Causes	Symptoms	Diagnosis and treatment
SIADH	SIADH is a syndrome characterized by excessive release of antidiuretic hormone (ADH or vasopressin) from the posterior pituitary gland or another source. The result is hyponatremia, and sometimes fluid overload	Nausea / vomiting Cramps Depressed mood Irritability Confusion Hallucinations Seizures, stupor or coma	Hyponatremia <135 mmol/l Effective serum osmolality<275mosm Urine sodium concentration>40mmol/litre Plasma uric acid <200;FeUrate>12% Absence of edematous disease likecardiac failure, liver cirrhosis,nephrotic syndrome. Normal adrenal and thyroid function
Cerebral salt wasting syndrome	Cerebral salt wasting syndrome is defined as therenal loss of sodium during intracranial disease leading to hyponatremia and a decrease in extracellular fluid volume Trauma Tumor Hematoma	The patient is Hypovolemic Hyponatremic	Treatment is Hydration and Sodium replacement
Adrenal insufficiency	Adrenal insufficiency Mineralocorticoid deficiency is present. Secondary or tertiary adrenal insufficiency will have preservedmineralocorticoid function owing to separate feedback mechanisms Adrenal insufficiency can be Primary Secondary Tertiary Common causes of primary adrenal insufficiency: Autoimmune Iatrogenic Drugs Adrenal hemorrhage Cancer Infection Congenital Secondary adrenal insufficiency: ( Aldosterone) levels normal Most common causes are: Traumatic brain injury (TBI) Panhypopituitarism Tertiary adrenal insufficiency Exogenoussteroid administration is the most common cause of tertiary adrenal insufficiency	Fatigue Muscle weakness Loss of appetite Weight loss Abdominal pain Diarrhea Vomiting Chronic disease is characterized by Weight loss Sparse axillary hair Hyperpigmentation Orthostatic hypotension. Acute addisonian crisis is characterized by: Fever Hypotension	The diagnosis of Addisons disease is made through rapid ACTH administration and measurement of cortisol. Lab findings include: White blood cell count with moderate neutropenia Lymphocytosis Eosinophilia Hyperkalemia Hypoglycemia Hyponatremia Morning low plasma cortisol. The definitive diagnosis is the cosyntropin or ACTH stimulation test. Acortisol level is obtained before and after administering ACTH. A normal person should show a brisk rise in cortisol level after ACTH administration. Management: The management of Addison disease involves: Gluocorticoid Mineralocorticoid Sodium chloride replacement. Adrenal crisis: In adrenal crisis,measure cortisol level,then rapidly administer Fluids Hydrocortisone
Hypopituitarism	Abnormality in anterior pituitary function Etiology is as follows: Pituitary tumors Sellar tumors Head trauma Infection Empty sella Infiltration Idiopathic Congenital	Signs and symptoms ofhypopituitarism vary, depending on the deficient hormone and severity of the disorder,some of the symptoms may be as follows: Fatigue Weight loss Decreased libido Decreased appetite Facial puffiness Anemia Infertility Cold insensitivity. Amenorrha Inability to lactate in breast feeding women Decreased facial orbody hair in men Short stature in children	History andphysical examination, including visual field testing, are important. The treatment of permanent hypopituitarism consists of replacement of the peripheral hormones Hydrocortisone DHEA Thyroxine Testosterone or oestradiol Growth hormone Surgery and/or Radiotherapy to restore normal endocrine function and quality of life Life long monitoring of serum hormone levels and symptoms of hormone deficiency or excess is needed in these patients
Hypothyroidism	Hypofunctioning of the thyroid gland due to multifactorial etiology ranging from congenital to autoimmune causes described below: Congenital Autoimmune Drugs Post surgery Post radiation Infiltrative e.g., amyloid	Fatigue Constipation Dry skin Weight gain Cold intolerance Puffy face Hoarseness Muscle weakness Elevated blood cholesterol level Bradycardia Myopathy Depression Impaired memory	Diagnosis of hypothyroidism is based on blood tests: T3(triiodothyronine) T4(Thyroxine) and TSH (thyroid stimulating hormone). Signs and symptoms are neither sensitive nor specific for the diagnosis. TSH is the most sensitive tool for screening,diagnosis and treatment follow up, whenpituitary is normal. The drug of choice for treatment is Levothyroxine
Psychogenic polydipsia	Also called as primary polydipsia is characterized bypolyuria and polydipsia. Causes are: Adverse effect of a medication Traumaticbrain injury Psychiatric disorders such as schizophrenia Defect in the hypothalamus	Polyuria Polydipsia Confusion Lethargy Psychosis Seizures and Sometimes, even death	Evaluation ofpsychiatric patients with polydipsia requires an evaluation for other medical causes of polydipsia, polyuria,hyponatremia, and the syndrome of inappropriate secretion of antidiuretic hormone. The management strategy inpsychiatric patients should include: Fluid restriction andbehavioral and pharmacologic modalities. The water deprivation test is the gold standard test

References

1. ↑ Patnaik MM, Deshpande AK (2008). “Diagnosis–Addison’s disease secondary to tuberculosis of the adrenal glands”. Clin Med Res. 6 (1): 29. doi:10.3121/cmr.2007.754a. PMC 2442022. PMID 18591375.
2. ↑ Bhattacharjee R, Sharma A, Rays A, Thakur I, Sarkar D, Mandal B, Mookerjee SK, Chatterjee SK, Chowdhury PR (2013). “Addison’s disease presenting with muscle spasm”. J Assoc Physicians India. 61 (9): 675–6. PMID 24772716.
3. ↑ Ray A, Sanyal D (2016). “A rare case of Addison’s disease due to bilateral adrenal histoplasmosis presenting with hypoglycaemia”. J Assoc Physicians India. 64 (1): 45–46. PMID 27727656.
4. ↑ Choudhary N, Aggarwal I, Dutta D, Ghosh AG, Chatterjee G, Chowdhury S (2013). “Acquired perforating dermatosis and Addison’s disease due to disseminated histoplasmosis: Presentation and clinical outcomes”. Dermatoendocrinol. 5 (2): 305–8. doi:10.4161/derm.22677. PMC 3772918. PMID 24194970.
5. ↑ Schimke KE, Greminger P, Brändle M (2009). “Secondary adrenal insufficiency due to opiate therapy – another differential diagnosis worth consideration”. Exp. Clin. Endocrinol. Diabetes. 117 (10): 649–51. doi:10.1055/s-0029-1202851. PMID 19373753.
6. ↑ Patel FB, Newman SA, Norton SA (2016). “Addisonian-Like Hyperpigmentation as an Indicator of Uncontrolled Congenital Adrenal Hyperplasia”. Skinmed. 14 (1): 53–4. PMID 27072733.
7. ↑ Seyberth HW (2016). “Pathophysiology and clinical presentations of salt-losing tubulopathies”. Pediatr. Nephrol. 31 (3): 407–18. doi:10.1007/s00467-015-3143-1. PMID 26178649.
8. ↑ Sayin B (2015). “Tacrolimus-Induced Salt Losing Nephropathy Resolved After Conversion to Everolimus”. Transplant Direct. 1 (9): e37. doi:10.1097/TXD.0000000000000538. PMC 4946484. PMID 27500237.
9. ↑ Yoshioka K, Nishio M, Sano S, Sakurai K, Yamagami K, Yamashita Y (2009). “Development of Severe Hyponatremia due to Salt-Losing Nephropathy after Esophagectomy for Esophageal Cancer”. Case Rep Med. 2009: 241283. doi:10.1155/2009/241283. PMC 2771150. PMID 19888422.

References

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

The prevalence of secondary adrenal insufficiency is approximately 15-28 per 100,000 individuals worldwide more common than Addison disease. The incidence increases with age; the median age at diagnosis is 60 years. There is no racial predilection. Women are more commonly affected by secondary adrenal insufficiency than male.

• The prevalence of secondary adrenal insufficiency is approximately 15-28 per 100,000 individuals worldwide more common than Addison disease.^[1]

• The incidence of secondary adrenal insufficiency increases with age; the median age at diagnosis is 60 years.

• There is no racial predilection to secondary adrenal insufficiency.

• Women are more commonly affected by secondary adrenal insufficiency than male.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

The most potent risk factor in the development of secondary adrenal insufficiency is infections, such as Tuberculosis. Other risk factors include genetic defects of adrenal gland, diabetes, and Vitiligo.

The following conditions increase the risk of adrenal insufficiency:

• Drugs
  • Chronic steroid therapy
  • Opiates
  • Antifungals- ketoconazole^[1]
• Genetic defects of adrenal gland
  • Congenital adrenal hyperplasia
• Other genetic defects
  • Combined pituitary hormone deficiency (CPHD)
• Diabetes
• Vitiligo
• Tuberculosis
• Amyloidosis
• AIDS-associated infections
• Cancer

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

If left untreated, secondary adrenal insufficiency can be life-threatening. Any stressful event or illness can cause a sudden worsening of symptoms, which can lead to severe dehydration and fatally low blood pressure and eventually death from adrenal crisis. Common complications include hypoglycemia, adrenal crisis, hypovolemic shock and cardiac arrest. Prognosis is generally good in patients with secondary adrenal insufficiency as long as they are on life-time hormonal therapy. Patients with secondary adrenal insufficiency must be closely monitored for compliance with medications as acute cases can be life-threatening and the mortality rates can go up to 95% in acute crisis.

If left untreated, secondary adrenal insufficiency can be life-threatening. Any stressful event or illness can cause a sudden worsening of symptoms, which can lead to severe dehydration and fatally low blood pressure and eventually death from adrenal crisis.

Complications of secondary adrenal insufficiency include:^[1]

• Hypoglycemia
• Adrenal crisis
• Hypovolemic shock
• Cardiac arrest

• Prognosis is generally good in patients with secondary adrenal insufficiency as long as they are on life-time hormonal therapy,^[2][3] or when the underlying cause is removed.
• Patients with secondary adrenal insufficiency must be closely monitored for compliance with medications as acute cases can be life-threating and the mortality rates can go up to 95% in acute crisis.
• For prognosis of secondary adrenal insufficiency where cause is hypopituitarism, click here.

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