Biomedical Science: Pathophysiology of Disease - Case Study Example

Case Study Based on the patient’s clinical presentation and laboratory results, what is the most probable diagnosis in this patient? How do you account for the hyponatremia, decreased bicarbonate and decreased serum osmolality? The aptient presented in a semicomatose state with no other symptomatology. The first differential diagnosis would be hypoglycemia, followed by electrolyte disturbances like hyponatremia. Initial investigations revealed hyponatremia, potassium on the upper-side normal limit and low free cortisol levels (5 microgram/dL, Normal: 10-34 micro g/dL), all of which point to the diagnosis of adrenocortico insufficiency. A high index of suspicion is essential for diagnosis. Adrenocorticodeficiency may be primary or secondary (Williams and Dluhy, 2008). Primary adrenocortico deficiency refers to Addison disease and occurs due to destruction of the adrenal glands (Williams and Dluhy, 2008). Secondary adrenocorticodeficiency occurs due to decreased production of adrenocorticotropin by the pituitary gland (Williams and Dluhy, 2008). This hormone is essential for stimulation of the adrenal glands to produce cortisol. Deficiency of this hormone causes decreased production of cortisol. Over a period of time, decreased stimulation of the adrenal glands results in shrinkage of the adrenal glands (Williams and Dluhy, 2008). In this patient, the most probable diagnosis is primary adrenocorticodeficiency or Addison disease and he is admitted in Addisonian crisis. Addison disease was first described by Thomas Addison and hence the name (Griffing and Odeke, 2009). The disease is rare. The incidence in Great Britain is about 30 per 1 million population (Griffing and Odeke, 2009). In Denmark, it has been reported as 60 per one million population and in the United States, 40-60 cases per one million population (Griffing and Odeke, 2009). The morbidity and mortality associated with the disease is mainly due to delay or failure in arriving at the diagnosis and failure to adequately replace appropriate corticosteroids. Untreated and inappropriately treated addisonian crisis eventually results in death. The deterioration may be triggered by adrenal hemorrhage, acute health condition or inadequate steroid replacement. The most common age of presentation is 30-50 years, although, in conditions like congenital adrenal hyperplasia, polyglandular syndromes and long-chain fatty acid metabolism disorders, the disease may occur earlier (Griffing and Odeke, 2009). The symptomatology of Addison disease is nonspecific and the onset is usually insidious. Some may even present for the first time in Addisonian cirsis as Mr.X. The acute presentation may be precipitated by various factors like stress, infections, surgery, trauma, vomiting, diarrhea, etc. Symptoms of acute presentation include nausea, vomiting, vascular collage, confusion, acute abdominal symptoms, hyperpyrexia and coma (Griffing and Odeke, 2009). Mr. X presented with semicoma. Chronic Addison disease may present as hyperpigmentation of mucus membranes and skin, vitiligo, progressive weakness, fatigue, weight loss and poor appetite (Griffing and Odeke, 2009). In Mr.X, weight loss was evident. Other symptoms of the chronic Addison disease are myalgia, flaccid paralysis, dizziness, muscle and joint pains, impotence and decreased libido. Physical examination in a patient with Addison disease may reveal hyperpigmentation, vitiligo, dehydration, orthostasis and hypotension (Griffing and Odeke, 2009). In Addison disease, there is decreased secretion of aldosterone also. Aldosterone is also a steroid hormone and is essential for reabsorption of socdium from distal nephron. Aldosterone increases the reabsorption of Na+ and water from urine and causes retention of Na+ and water in the extracellular fluid (ECF), thus expanding the ECF volume. This is primarily due to its action on the principal cells of the collecting ducts of the kidney. The Na+ is exchanged for K+ and H+. Thus when there is decreased production of this hormone, hyponatremia occurs. Bicarbonate is reabsorbed as a cotransporter with sodium. Thus, when sodium reabsorption decreased, bicarbonate reabsorption also decreases, resulting in decreased bicarbonate. Sodium is the most important electrolyte necessary for maintaining normal osmolality. It is the major solute in extracellular fluids, so it effectively determines the osmolarity of extracellular fluids. Regulation of osmolarity is achieved by balancing the intake and excretion of sodium with that of water. It is integrated with regulation of volume, because changes in water volume alone have diluting or concentrating effects on the bodily fluids. Hyponatremia, secondary to decreased aldosterone secretion leads to decreased serum osmolality in Addison disease. Since the patient is in Addisonian crisis, he must be admitted to Intensive Care Unit. IV access must be gained immediately and isotonic sodium chloride must be instituted to correct dehydration and restore volume deficit. After taking blood for various tests and performing the ACTH challenge test, 100 mg of hydrocortisone must be administered after diluting with 100 ml of isotonic sodium chloride (Griffing and Odeke, 2009). It must be given every 6-8 hours. Infusion method is better than bolus because it maintains a steady level of plasma cortisol. The dose of hydrocortisone can be reduced after 2-3 days. The patient must be monitored for blood pressure response. After adequate improvement is noted, hydrocortisone can be made oral and minerocorticoid replacement therapy instituted. The most commonly used mineralocorticoid is 9-alpha-fludrocortisone (Griffing and Odeke, 2009). It is given at doses 0.05-0.10 mg per day (Griffing and Odeke, 2009). At the time of discharge, the patient must be advised about intake of both the medications. The patient must also be advised to to increase the intake of salt in hot climatic conditions. Regular follow up is very essential for this patient. Also, in times of stress, infection, trauma and surgery, the dose of steroids must be increased (Griffing and Odeke, 2009). 2. What is the significance of the ACTH stimulation test shown in the second table? To arrive at a diagnosis of adrenocorticoid deficiency, ACTH stimulation test must be done. This test assesses the functional capacity of the adrenal cortex to produce cortisol. The principle behind this test is that "within 15-30 minutes of ACTH infusion, the normal adrenal cortex releases 2-5 times its basal plasma cortisol output" (Griffing and Odeke, 2009) and "an increase in the plasma cortisol and aldosterone levels above basal levels after ACTH injection reflects the functional integrity of the adrenal cortex" (Griffing and Odeke, 2009). In Mr.X, the baseline cortisol level was cortisol level was 7 microgram per dl. After challenging with ACTH, at 30 minutes, the level continued to be the same; and after 60 minutes, the level was 6 microgram per dl. This means that despite administration of ACTH, the cortisol levels did not increase, suggestive of damage to the adrenal cortex. This is indicative of primary adrenocorticoid deficiency or Addison disease. 3. What other test is useful in the differential diagnosis? Other than the ACTH stimulation test, the hypothalamic-pituitary axis may be evaluated by performing nother 2 important tests, the insulin tolerance test and the metyrapone test. Insulin tolerance test is a very sensitive test for adrenal insufficiency. The test involves induction of hypoglycemic stress for induction of cortisol stimulation. Hypoglycemic stress is induced by challenging the patient with 0.1-0.15U/kg of insulin. The peak response of cortisol in serum is measured after a few minutes of administering insulin. If the cortisol level is less than 18 mcg per dl even when the glucose level is less than 40 mg/dl, it is suggestive of adrenal insufficiency. This useful test is hower not recommended in critically ill patients and must be administered with caution and constant monitoring (Liotta and Elston, 2009). In Metyrapone test, the cortisol production pathway is disrupted by inhibiting the enzyme 11-B hydroxylase that is essential for the conversion of 11-deoxycortisol to cortisol by administration of 30 mg per kg of metyrapone. The cortisol and 11-deoxycortisol levels are measured after 8 hours of administering metyrapone. Normally, the 11-deoxycortisone levels rise to more than 7mg per dl. In adrenal insufficiency, the levels are below 7 mg per dl (Liotta and Elston, 2009). Other tests which may be done are BUN and creatinine which may be elevated due to decreased renal plasma flow and decreased glomerular filtration rate, liver function tests to reveal glucocorticoid-responsive liver dysfunction. Complete blood count is necessary to rule out eosinophilia (Munver and Volfson, 2006). Prolactin testing may be done. In Addison disease, modest hyperprolactinemia may be seen due to hyperresponsiveness to thyrotropin-releasing hormone and absence of thyrotropin-releasing hormone. Mantoux test must be done to rule out tuberculosis (Ten, New and Maclaren, 2001). CT scan of the head and abdomen is normal in Mr.X. In some patients with Addisons disease, CT abdomen may reveal bilateral enlargement, calcification, granulomas or even atrophy (Griffing and Odeke, 2009). 4. In this case, why isn’t it part of panhypopituitarism? Hypopituitarism is a clinical syndrome that occurs due to deficiency of the production of ptuitary hormone (Mulinda, 2009). The condition occurs due to disorders of the pituitary gland or the hypothalamus. The pituitary gland secretes several hormones, the most important of which are antidiuretic hormone, thyroid stimulating hormone, prolactin, luteinizing hormone, follicle stimulating hormone and adrenocorticotrophic hormone. When there is decreased production of all the hormones, the condition is called panhypopituitarism. There are 2 reasons why the patient does not have panhypopituitarism. The first reason is because the thyroid profile including the thyroid stimulating hormoone test is normal. The second reason is that administration of ACTH did not lead to an increase of cortisol levels suggestive of the fact that the pathophysiology of the condition is in adrenal cortex and notin the pituitary or hypothalamus. Thus, the main pathology in the patient lies in the adrenal cortex. 5. What is the most common finding in the adrenal gland in this condition? What is the probable cause? Adrenal glands are important hormone secreting glands located in the upper poles of the kidneys. They consist mainly of 2 parts, the adrenal cortex and the adrenal medulla. The adrenal cortex has 3 zones, the zona glomerulosa, zona fasciculata and zona reticularis. The cortex is secretes aldostrerone, sex hormones and cortisol. All the hormones are synthesised from cholesterol-steroid ring. In Addison disease, the histopathology of the adrenal glands depends on the type of insult to the glands. The most common cause of Addison disease which accounts for 90 percent of the cases is the idiopathic autoimmune type. In this type, the cortex is mainly affected and the medulla is spared. Symptoms appear only when more than 90 percent of both the glands are affected. CT Scan of the abdomen may be normal or may demonstrate atrophied glands. Histopathology will reveal atrophic glands with marked lymphocytic infiltration and capsular fibrosis. When the condition is caused due to tuberculosis, granulomas may be see in histopathology. When histoplasmosis is the cause, calcification may be noted in the adrenal cortex on histopathologic examination (Griffing and Odeke, 2009). 6. What other less common conditions can cause this condition? Other causes include chronic granulomatous disease due to conditions like tuberculosis, hematologic malignancies, metastases, infiltrative metabolic disease, acquired immunodeficiency syndrome, irradiation and drugs (Griffing and Odeke, 2009). Idopathic autoimmune Addison disease may occur in conjunction with other autoimmune diseases like type-1 diabetes mellitus, celiac disease, vitiligo, myasthenia gravis, chronic active hepatitis, etc. The differential diagnoses of this condition are adrenal hemorrhage, hisotplasmosis, sarcoidosis, tuberculosis, adrenal crisis, eosinophilia and C-17 hydroxylase deficiency (Griffing and Odeke, 2009). References Ganong, W.F., 2003. Review of Medical Physiology. 21st edition. New York: Mc Graw Hill. Griffing, G.T., and Odeke, S. (2009). Addison disease. Emedicine from WebMD. Retrieved on 12 Feb, 2010 from http://emedicine.medscape.com/article/116467-overview Mulinda, J.R. (2009). Hypopituitarism. Emedicine from WebMD. http://emedicine.medscape.com/article/122287-overview Munver, R., and Volfson, I.A. (2006). Adrenal insufficiency: diagnosis and management. Current Urology Reports, 7, 80–85. Ten, S., New, M., Maclaren, N. (2001). Clinical Review 130: Addison’s disease. Journal of Clinical Endocrinology & Metabolism, 86(7), 2909–2922 Williams, G.H., and Dluhy, R.C. (2008). Disorders of the adrenal cortex. In: Braunwald E, ed. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill Professional, pg. 2247–2268 Read More