notes by dr Claudio Italiano
The adrenal medulla synthesizes the norepinephrine, epinephrine and dopamine catecholamines from the amino acid tyrosine. The norepinephrine, the most important catacola-minine produced by the adrenal medulla, has a predominantly α-agonist action, thus causing vasoconstriction. Epinephrine acts primarily on Beta receptors presenting positive inotropic and chronotropic cardiac effects (ie, increases contraction strength and speed), causing peripheral vasodilatation and increasing plasma glucose concentrations in response to hypoglycemia (stress hormone).
The action of circulating dopamine is currently unclear. While norepinephrine is synthesized in the central nervous system and in postganglion sympathetic neurons, epinephrine is almost entirely synthesized in the adrenal medulla. The contribution of the adrenal medulla to the synthesis of norepinephrine is relatively small.
Bilateral adrenalectomy causes only small changes in circulating norepinephrine levels, although the levels of epinephrine are drastically reduced. Therefore, adrenal medullary hypofunction has a minor physiological impact, while catecholamine hypersecretion produces the clinical syndrome of pheochromocytoma.
Pheochromocytoma is a generally benign tumor that originates from the chromaffin cells of the neuroectoderm, which is part of the sympathetic system. Although phaeochromocytomas can affect every sympathetic ganglion present in the body, more than 90% originate from the adrenal medulla. The majority of ex-transurrenal tumors are observed in the mediastinum or abdomen. Bilateral adrenal pheochromocytomas are observed in about 5% of cases and may be part of familial syndromes. The feo-chromocitoma is part of multiple endocrine neoplasms of type 2A or 2B. The first (Sipple syndrome) is characterized by medullary thyroid carcinoma, hyperparathyroidism and pheochromocytoma; the second is characterized by medullary thyroid carcinoma, by mucosal neurinomas, by intestinal ganglioneuromas, by a marfanoid habitus and by pheochromocytoma. Pheochromocytomas are also associated with neurofibromatosis, cerebello-retinic angiogioblastosis (von Hippel-Lindau syndrome) and tuberous sclerosis.
Since the majority of pheochromocytomas secretes norepinephrine as the main catecholamine, hypertension (often paroxysmal) is the most common clinical feature. Other symptoms, including the triad of headache, palpitations and sweating, may include redness, anxiety, nausea, fatigue, weight loss and abdominal and thoracic pain.
These symptoms can be triggered by emotional stress, physical exercise, anesthesia, abdominal pressure or the ingestion of food containing tyramine. Some patients have orthostatic hypotension. Large fluctuations in blood pressure often occur and hypertension associated with pheochromocytoma does not usually respond to standard antihypertensive drugs.
The diagnosis of phaeochromocytoma is given thanks to the demonstration, during the hypertensive crisis, of a high urinary excretion of catecholamines or their metabolites, metanephrines and vanilmandelic acid. The evaluation of urinary levels of metanephrine is probably the only most reliable diagnostic test, but usually the total urinary catecholamines, epinephrine, norepinefrina and vanilmandelic acid are also measured. The determination of plasma catecholamines may also be useful. The blood sample should be taken under conditions of hypertension and when the patient is in a supine position and after inserting a needle-cannula in order to avoid stress related to perforation of the vein. Plasma levels of norepinephrine greater than 500 pg / ml or epinephrine above 500 pg / ml are suggestive of pheochromocytoma. If the values are at the high limits of normality, there is an indication to carry out a suppression test with clonidine. In this trial, clonidine is administered orally (0.3 mg / kg) and plasma catecholamines are assayed before administration and after 3 hours. Normal individuals show a decrease in catecholamine levels up to normal values, while patients with pheochromocytoma do not show changes or increase catecholamine concentrations. Once the diagnosis of phaeochromocytoma has been established, a CT scan of the adrenal glands should be performed. Most intrasurrenic pheochromocytomas are readily displayed.
If CT findings are negative, extra-adrenal pheochromocytomas can often be localized by scintigraphy with 131I-metaiodobenzylguanidine (131I-MIBG), either by scintigraphy with radiolabeled octreotide or by abdominal MR. If the lesion can be localized, the treatment of the pheochromocytoma is surgical. Preoperative patients should be treated with a-blockers in order to improve surgical morbidity and mortality: phenoxybenzamine and a-methyl-p-tyrosine (a tyrosine-hydroxylase inhibitor, the enzyme limiting catecholamine biosynthesis) should be administered for 1-2 weeks before surgery. Beta-adrenergic antagonists should be used during surgery. Approximately 5-10% of pheochromocytomas are malignant. 131I-MIBG or chemotherapy may be useful, but the prognosis is poor. A-methyl-p-tyrosine can be used to reduce catecholamine secretion by the tumor.