Case #5 Ephraim R. Caangay Pharmacology B February 7, 2007

The Case GP, 23 year old female, sought consultation at Fatima Medical Center due to intermittent attacks of severe headaches, palpitations and sweating. PE revealed an elevated BP = 180/100 and tachycardia (CR = 100/min). Attending physician requested for a 24 hour urine VMA determination which revealed an elevated result = 15 mg/24 hours.

Initial Differential Diagnosis Cocaine Abuse Migraine – pain in the head (usually unilateral), vertigo, nausea and vomiting, photophobia, and scintillating appearances of light. Possible CVA – “intermittent attacks” wrong presentation Brain Tumor – “intermittent attacks” wrong presentation Angina Pectoris Anxiety Disorders Hyperthyroidism (–)

The Case (cont’) Attending physician requested for a 24 hour urine VMA determination which revealed an elevated result = 15 mg/24 hours.

VMA? VMA – Vanillyl Mandelic Acid The major urinary metabolite of adrenal and sympathetic catecholamines; elevated in most patients with pheochromocytoma.

Pheochromocytoma Considered an endocrinologic secondary cause of hypertension A functional chromaffinoma, usually benign, derived from adrenal medullary tissue cells and characterized by the secretion of catecholamines, resulting in hypertension Hypertension may be paroxysmal and associated with attacks of palpitation, headache, nausea, dyspnea, anxiety, pallor, and profuse sweating. Pheochromocytomas are not innervated, and catecholamine release is not precipitated by neural stimulation

Incidence Race – can occur in any race Gender – occurs equally in males and females Age – can occur at any age, with peak between 30 – 50.

Biological Effects Of Catecholamines Stimulation of alpha-adrenergic receptors –elevated blood pressure –increased cardiac contractility –glycogenolysis –Gluconeogenesis –intestinal relaxation Stimulation of beta-adrenergic receptors –increase in heart rate –Increase in contractility.

Typical Clinical History Spells characterized by: Headaches Palpitations diaphoresis All in association with severe hypertension (possibly paroxysmal). Typical progressively worsen, increase in frequency Without these symptoms and hypertension, can rule out pheochromocytoma diagnosis.

Other Clinical Signs Hypertension (paroxysmal in 50% of cases) Postural hypotension: Hypertensive retinopathy Weight loss Pallor Fever Tremor Neurofibromas Café au lait spots Tachyarrhythmias Pulmonary edema Cardiomyopathy Ileus

Lab Diagnosis Perform a 24-hour urine collection for creatinine, total catecholamines, vanillyl mandelic acid, and metanephrines. –Measure creatinine in all collections of urine to ensure adequacy of the collection. –Metanephrine levels are considered the most sensitive and specific test for a pheochromocytoma, while vanillylmandelic acid is the least specific test and has a false- positive rate greater than 15%. –The collection container should be dark and acidified and should be kept cold to avoid degradation of the catecholamines.

Imaging Studies Perform imaging studies after lab diagnosis of a pheochromocytoma. MRI is preferred over CT scanning. –sensitivity of up to 100% in detecting adrenal pheochromocytomas, –does not require contrast, –does not expose the patient to ionizing radiation. –MRI is also superior to CT scanning for detecting extra-adrenal pheochromocytomas. CT –an accuracy of 85-95% for detecting adrenal masses with a spatial resolution of 1 cm or greater. –less accurate for lesions smaller than 1 cm.

MRI Pheochromocytoma. Axial T2-weighted MRI showing large left suprarenal mass of high signal intensity on a T2-weighted image representing a pheochromocytoma.

Pheochromocytoma. Abdominal CT scan demonstrating left suprarenal mass of soft tissue attenuation representing a paraganglioma.

Histologic Findings Pheochromocytomas vary from 2 g to 3 kg but, on average, weigh 100 g (normal: 4-6 g). These tumors are well encapsulated, highly vascular, and appear reddish brown on cut section. the tumor cells are arranged in balls and clusters separated by endothelial-lined spaces: zellballen. The cells vary in size and shape and have finely granular basophilic or eosinophilic cytoplasm. The nuclei are round or oval with prominent nucleoli. Nuclear giantism and hyperchromasia are common.

Treatment Surgical resection, but first need to medically stabilize. –Preferable to remove only affected adrenal gland –If both are removed, patient requires lifetime glucocorticoid and mineralocorticoid replacement therapy Use non-selective alpha-adrenergic antagonists to control hypertension –DOC: phenoxybenzamine –Phentolamine If significant tachycardia is experienced after alpha blockade, give non-selective beta- adrenergic blockers –DOC: Propranolol

Prognosis Because of excessive catecholamine secretion  precipitate life-threatening hypertension or cardiac arrhythmias. If Dx of is overlooked, the consequences could be disastrous, even fatal However, if a pheochromocytoma is found, it is potentially curable