History

Fact Explanation
Fatigue [1] It is a cardinal symptom. Due to adrenocortical insufficiency caused by gradual adrenal destruction. Symptoms have insidious onset. Along with the progressive impairment of adrenal function, the patient becomes progressively fatigued. [1]
Anorexia, Nausea, Vomiting [1] Due to gastrointestinal abnormalities due to progressive adrenocortical insufficiency. [1]
Weight loss [1] Due to Gastrointestinal symptoms and due to chronic disease. [1]
Postural dizziness [2] Due to hypovolaemia and sodium loss. [2]
Darkening of skin complexion [2] Due to skin pigmentation. Present in over 90% of patients. ACTH secretion is increased in Addison's disease, therefore melanocyte stimulating hormone like substances which are secreted along with ACTH are also increased and causes pigmentation by dispersion of melanocytes. [2]
Darkening of mucosa of the mouth [2] Also due to pigmentation caused by melanocytes like substances.[2]
Episodes of faintness or syncope [1] Caused by hypoglycemia or hypotension. [1]
History of other Autoimmune diseases such as Type 1 Diabetes mellitus, Thyroiditis, Vitiligo [2] Addison's disease can be caused by Autoimmune adrenalitis causing adrenal cortex destruction [2]
Symptoms of Pulmonary Tuberculosis [3] Tuberculosis remains the most common cause of Addison disease worldwide. Symptoms of Chronic cough, Haemoptysis, Evening pyrexia, loss of weight. Also contact history of Tuberculosis [1], [3]
References
  1. LONGO DL, FAUCI AS, KASPER DL, HAUSER SL, JAMESON JL, LOSCALZO J. Harrison's Principles of Internal Medicine. 18th Edition. 2012. New York. McGrawHill-Medical
  2. KUMAR P, CLARK M. Kumar and Clark's Clinical Medicine. 8th Edition. 2012. Edinburgh. Saunders-Elsevier.
  3. CHAKERA AJ, VAIDYA B. Addison Disease in Adults: Diagnosis and Management. The American Journal of Medicine (2010) 123, 409-413.

Examination

Fact Explanation
General wasting [1] Due to Chronic disease, hypoglycaemia and salt loss. [1]
Dehydration [1] Due to sodium loss and hypovolaemia. [1]
Pigmentation [1] Specially of palmar creases and of new scars. [1] May appear as dull, slaty, grey-brown. [1] Hyper pigmentation is absent if adrenal destruction is rapid, eg; in bilateral adrenal hemorrhage [2]
Buccal pigmentation [1] Above reasons of pigmentation.
Postural Hypotension [1] Due to sodium loss and hypovolaemia. [1]
Loss of body hair [1] Due to loss of adrenal androgens. [2]
Goitre May be associated with other autoimmune conditions such as thyroiditis. [1]
Vitiligo May be associated with other autoimmune conditions such as vitiligo. [1]
Respiratory system - Signs of Pulmonary Tuberculosis Tuberculosis remains the most common cause of Addison disease worldwide. [3] Pleural effusions, bronchial breathing over upper zones due to cavitation, etc [2]
References
  1. KUMAR P, CLARK M. Kumar and Clark's Clinical Medicine. 8th Edition. 2012. Edinburgh. Saunders-Elsevier.
  2. LONGO DL, FAUCI AS, KASPER DL, HAUSER SL, JAMESON JL, LOSCALZO J. Harrison's Principles of Internal Medicine. 18th Edition. 2012. New York. McGrawHill-Medical
  3. CHAKERA AJ, VAIDYA B. Addison Disease in Adults: Diagnosis and Management. The American Journal of Medicine (2010) 123, 409-413.

Differential Diagnoses

Fact Explanation
Hereditary Haemochromatosis [1] Can also cause diffuse skin pigmentation. However other features of Iron overload will be present such Liver damage (Cirrhosis), Heart failure, etc will be present [2]
Hyperthyroidism [1] Can also cause diffuse skin pigmentation. However presence of a Goitre may help in diagnosing Hyperthyroidism. [3]
Prolonged high dose Glucocorticoid Therapy [4] leads to suppression of endogenous cortisol production. Recovery of endogenous cortisol production occurs after stopping the exogenous glucocorticoid, however the time period to recovery can vary. The patient is at risk of developing adrenal insufficiency if the glucocorticoid is stopped abruptly. [4]
ACTH deficiency [5] adrenal crisis can be caused by isolated ACTH deficiency [5], [6]
References
  1. STULBERG DL, CLARK N, TOVEY D. Common Hyperpigmentation Disorders in Adults: Part I. Diagnostic Approach, Caféau Lait Macules, Diffuse Hyperpigmentation, Sun Exposure, and Phototoxic Reactions. American Family Physician. 2003 Nov 15;68(10):1955-1961
  2. PIETRANGELO A. Hereditary Hemochromatosis — A New Look at an Old Disease. The New England Journal of Medicine 2004; 350:2383-2397June 3, 2004DOI: 10.1056/NEJMra031573
  3. MILLER R, ASHKAR FS, JACOBI J. Hyperpigmentation in Thyrotoxicosis. The Journal of the American Medical Association. 1970;213(2):299. doi:10.1001/jama.1970.03170280057021
  4. LANSANG MC. Glucocorticoid-induced diabetes and adrenal suppression: How to detect and manage them. Cleveland Clinic Journal of Medicine November 2011 vol. 78 11 748-756 doi: 10.3949/ccjm.78a.10180
  5. SHIMIZU M, MONGUCHI T, TAKANO T, MIWA Y. Isolated ACTH deficiency presenting with severe myocardial dysfunction. Journal of Cardiology Cases Volume 4, Issue 1 , Pages e26-e30, August 2011.
  6. KUMAR P, CLARK M. Kumar and Clark's Clinical Medicine. 8th Edition. 2012. Edinburgh. Saunders-Elsevier.

Investigations - for Diagnosis

Fact Explanation
09:00 hours Plasma ACTH level [1] A high Plsma ACTH level (>80ng/l) with low or low-normal Cortisol confirms primary hypoadrenalism [1]
References
  1. KUMAR P, CLARK M. Kumar and Clark's Clinical Medicine. 8th Edition. 2012. Edinburgh. Saunders-Elsevier.

Investigations - Fitness for Management

Fact Explanation
Hyponatraemia [1] Due to many reasons. 1.) Aldosterone deficiency causes loss of sodium with urine 2.) movement of sodium into the intracellular compartment. 3.) Elevated plasma vasopressin and angiotensin II levels may contribute to the hyponatremia by impairing free water clearance [2]
Hyperkalaemia [1] Due to many reasons such as, 1.) aldosterone deficiency, 2.) impaired glomerular filtration, 3.) acidosis [2]
Hypoglycaemia [1] Due to Adrenal insufficiency causing low glucocorticoid levels. Glucocorticoids are necessary for Gluconeogenesis. Therefore Frequent hypoglycemia is seen in Addison's disease due to reduced gluconeogenesis. [1] Patients with Addison's disease also suffer from severe anorexia, nausea and vomiting therefore low level of nutrition also contributes to hypoglycemia. [2]
Hypercalcaemia [1] Present in 10% - 20%, causes not clear [2]
Anaemia [1] Usually Normochromic normocytic [2] due to anemia of Chronic disease. These patients also suffer from Anorexia, nausea and vomiiting frequently [2] therefore reduced nutrition may contribute to Iron deficiency Anemia. Addison's disease is also associated with other auto immune diseases therefore Pernicious anemia may be associated and cause anemia [2]
References
  1. KUMAR P, CLARK M. Kumar and Clark's Clinical Medicine. 8th Edition. 2012. Edinburgh. Saunders-Elsevier.
  2. LONGO DL, FAUCI AS, KASPER DL, HAUSER SL, JAMESON JL, LOSCALZO J. Harrison's Principles of Internal Medicine. 18th Edition. 2012. New York. McGrawHill-Medical

Investigations - Followup

Fact Explanation
Serum Cortisol levels [1] Adequacy of Glucocorticoid dose is assumed by normal cortisol levels during the day while on hydrocortisone replacement. Along with Clinical well being and restoration of weight [1]
Serum electrolytes - Sodium, Potassium [1] Used as a para meter for adequacy of Fludrocortisone replacement is assessed by restoration of electrolytes to normal levels [1]
Plasma renin activity [1] Used as a para meter for adequacy of Fludrocortisone replacement is assessed by suppression of Renin activity to normal levels [1]
References
  1. KUMAR P, CLARK M. Kumar and Clark's Clinical Medicine. 8th Edition. 2012. Edinburgh. Saunders-Elsevier.

Investigations - Screening/Staging

Fact Explanation
Short ACTH stimulation test [1] Screening test for Addison's disease, however Impaired cortisol response only confirms presence of hypoadrenalism but does not help in differentiating from Addison's disease, ACTH deficiency, Iatrogenic suppression by steroid medication as a cause of hypoadrenalism [1]
single cortisol measurements [1] Little value. However a random cortisol level below 100nmol/l during the day is highly suggestive of hypoadrenalism [1]
Adrenal antibodies [1] Present in many cases of autoimmune adrenalitis [1]
Chest Xray [1] May show evidence of Pulmonary tuberculosis [1] In earlier times tuberculosis was responsible for 70–90% of cases, but the most frequent cause now is idiopathic atrophy [2]
Abdominal Xray [1] May show evidence of Adrenal calcification. [1] In earlier times, tuberculosis was responsible for 70–90% of cases, but the most frequent cause now is idiopathic atrophy [2]
Plasma Renin activity [1] High due to Low serum aldosterone [1]
References
  1. KUMAR P, CLARK M. Kumar and Clark's Clinical Medicine. 8th Edition. 2012. Edinburgh. Saunders-Elsevier.
  2. LONGO DL, FAUCI AS, KASPER DL, HAUSER SL, JAMESON JL, LOSCALZO J. Harrison's Principles of Internal Medicine. 18th Edition. 2012. New York. McGrawHill-Medical

Management - General Measures

Fact Explanation
Managment of Acute Hypoadrenalism [1] Intra venous fluids (Normal saline), Given with IV Hydrocortisone, Correction of Low blood Glucose, Monitoring vital parameters till stable [1]
Dehydroepiandrosterone (DHEA) [1] To assist in alleviating hypogonadism [1]
References
  1. KUMAR P, CLARK M. Kumar and Clark's Clinical Medicine. 8th Edition. 2012. Edinburgh. Saunders-Elsevier.

Management - Specific Treatments

Fact Explanation
Hydrocortisone [1] As Glucocorticoid replacement therapy. 20 -30mg daily, eg - 10mg on waking, 5mg at 12 noon, 5mg at 18:00 hours [1]
Prednisolone [1] As Glucocorticoid replacement therapy. 7.5mg daily. eg - 5mg on waking, 2.5mg at 18:00 hours. [1]
Fludrocortisone [1] As Mineralocorticoid replacement therapy. 50-300 micrograms daily [1]
Treatment of Tuberculosis if it is the cause of Hypoadrenalism [2] Anti-tuberculosis therapy (isoniazid, rifampin, pyrazinamide and ethambutol) along with hydrocortisone and Fludrocortisone supplementation [2]
References
  1. KUMAR P, CLARK M. Kumar and Clark's Clinical Medicine. 8th Edition. 2012. Edinburgh. Saunders-Elsevier.
  2. PATNAIK MM, DESHPANDE AK. Diagnosis–Addison’s Disease Secondary to Tuberculosis of the Adrenal Glands. Clinical Medicine and research. May 2008; (6) 1:29