Differentiating Secondary adrenal insufficiency from other diseases

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

Overview

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

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, histoplasmosis	+	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 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)	–	–	–	–	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 Gitelman syndrome Drugs- Tacrolimus	++	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

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