Case Study Team F

JENNIFER BORKEYDAHARSH RANA HUY LE

Patient HistoryA 55-year-old Caucasian female suffered from metatarsal stress fractures in both feet. She had gained about 20 pounds over the last 2 years. Physical exam revealed a blood pressure of 150/90 mm Hg. On physical exam, physician noticed that she had a moon face, dorsal fat pads and purple streaks on her skin. Her bone mineral density studies showed a low bone density. The initial laboratory results indicated a potassium level of 3.1 mEq/L (normal range: 3.6-4.8 mEq/L) and a glucose level of 134 mg/dL (normal range: 70-100 mg/dL). Arterial blood gas testing show a pH of 7.55 (normal range: 7.35-7.45) and bicarbonate of 32.3 mEq/L (normal range: 22-26 mEq/L). BUN and creatinine levels were normal. CBC results were unremarkable.

Patient History(Cont.) Patient Follow UpA 24-hour urine collection of 4150 mL that contains 5210 ug/24 h of cortisol (reference range, 3.5-45 ug/24 h) and her serum cortisol level was 40.5 ug/dL (reference range, 5-25 ug/dL). Her plasma ACTH was 143 pg/mL (reference range, 10-60 pg/mL).

MRI imaging revealed a possible pituitary microadenomaHistological examination of the tumor revealed a microadenoma

Differential Diagnosis Symptoms typical of Cushings syndrome or hypercortisolism Causes of Hypercortisolism- Primary Cushings syndromeIncreased cortisol production from the adrenal gland causes decreased production of ACTH from the anterior pituitary ACTH independent source: adrenal tumor, excessive treatment with glucocorticoids - Secondary Cushings disease Increased ACTH production from the anterior pituitary causes increased cortisol production from adrenal glandACTH dependent source: ACTH secreting pituitary tumor or ectopic tumor- Pseudo-Cushings syndrome due to chronic alcoholism, obesity or depression

Mechanism of hypertension, hypokalemia, and metabolic alkalosis

Cortisol functions mainly as glucocorticoid, but has increased mineralocorticoid action when present in excess High cortisol levels leads to substrate saturation of 11 beta-hydroxysteroid-dehydrogenase 2 (11bHSD2) - enzyme that converts active cortisol to inactive cortisone, highly expressed in the renal cortex Excess active cortisol acts on mineralocorticoid receptors in the renal tubules resulting in effects similar to aldosterone Increased sodium reabsorptionIncreased potassium and hydrogen ion excretion with reabsorption of bicarbonate hypokalemia and metabolic alkalosis Glucocorticoid excess also thought to increase expression of angiotensin II receptors, enhance vasoconstriction and inhibit vasodilation hypertension

AssessmentRounded moon faceDorsal fat pads between shoulder "Buffalo HumpWeight gain Glucocorticoid Stimulation of liver gluconeogenesis hyperglycemiaRaises blood glucose levels by suppressing secretion of insulinInhibition of glucose uptake in muscle and adipose tissueStimulation of fat breakdown in adipose tissue affects distribution and metabolism of protein and fat

Assessment(Cont.) Metatarsal stress fractures in both feetLow bone density Excessive Glucocorticoids decrease the bone collagenous matrix Reduce bone synthesis and increase its degradation.inhibits the replication of cells of the osteoplastic lineage, decreases the production of new osteoplastic cells and induces apoptosis of osteoblasts and osteocytes and this contributes to a decreased number of mature osteoblasts. Purple streaks on the skin Excessive ACTH productionCollagen synthesis deficiency , resulting in thin and fragile skin. ACTH binds to melanocyte-stimulating hormone, causing hyperpigmentation

Follow up Assessment Serum Cortisol Level: High (40ug/dL) Excessive Production of Cortisol by Adrenal CortexResonates with the presence of High plasma ACTH concentration (143 pg/mL)Plasma ACTH > 10 pg/mL indicates an ACTH dependent cause

24-hr Urine Cortisol: Very High (5210ug/24 h) Excessive Cortisol Production by Adrenal Gland Measure of Free Cortisol concentration (not bound to CBG or other proteins)24 Hour collection, since cortisol production is diurnal and episodicLevels >4 times the upper limit of normal indicates hypercortisolism (ULN= 45 g/24h) MRI revealed possible Pituitary Microadenoma Confirmed by Histological examination of the TumorThese tumors may secrete hormones (ACTH)Suppressed Negative Feedback

Final Diagnosis Secondary Cushings disease due to pituitary microadenoma

Prognosis & Treatment PrognosisDepends on the nature of tumor and severity of hypercotisolismControl of persistent hypercotisolism by medication or surgeryPt. with Microadenoma or ectopic tumor may have a poor prognosisFatal if not treated due to:Cardiovascular, thromboembolic, or hypertensive complications or infections

TreatmentDriven by the primary causeTranssphenoidal Surgery Microadenomectomy (preferred)Medical Therapy Adrenal enzyme inhibitor, adrenolytic agents, etc.Other methods such as pituitary irradiation available.

Epidemiology(Steffensen)(Tritos, N. A. et al)

Works CitedBernard K, Olugbenga Babatunde Ol. Cushings Syndrome: Review of Clinical Signs. HospitalPhysician 2008Mancini T, Doga M, Mazziotti G, Giustina A. Cushing's syndrome and bone. Pituitary. 2004;7(4):249-52.Nieman (2013, January 31). Establishing the diagnosis of Cushing's syndrome. Retrieved October 27, 2014, from uptodatewebsite: http://www.uptodate.com.libux.utmb.edu/contents/establishing-the-diagnosis-of-cushings-syndrome?source=preview&search=cushing%27s+laboratory&selectedTitle=1~150&language=en-US&anchor=H6#H7.Nieman (2014, August 29). Overview of the treatment of Cushing's syndrome. Retrieved October 27, 2014, from uptodatewebsite: http://www.uptodate.com.libux.utmb.edu/contents/establishing-the-diagnosis-of-cushings-syndrome?source=preview&search=cushing%27s+laboratory&selectedTitle=1~150&language=en-US&anchor=H6#H7 Tritos, N. A. et al. (2011) Management of Cushing disease Nat. Rev. Endocrinol. doi:10.1038/nrendo.2011.12Steffensen C, Bak AM, Rubeck KZ, Jrgensen JO. Epidemiology of Cushing's syndrome. Neuroendocrinology. 2010;92 Suppl 1:1-5.Castinetti F, Morange I, Devolx B, Brue T. Cushings disease. Orphanet J Rare Dis. 2012; 7:41. doi:10.1186/1750-1172-7-41.Singh Y, Kotwal N, Menon AS. Endocrine hypertension- Cushings syndrome. Indian J Endocrinol Metab. 2011; 15(Suppl4): S313-S316. doi:10.4103/2230-8210.86973.Coe SG, Tan WW, Fox TP. Cushings Syndrome Due to Ectopic Adrenocorticotropic Hormone Production Secondary to Hepatic Carcinoid: Diagnosis, Treatment, and Improved Quality of Life. J Gen Intern Med. 2008; 23(6):875-878. doi:10.1007/s11606-008-0587-z.

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