Main syndromes

A compilation of the main syndromes in medical practice.
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Julio Libman, Astrid M. Libman 

 

Pheochromocytomas are catecholamine-producing tumors derived from chromaffin cells. They can originate in the adrenal medulla or outside of it, in places where there is sympathetic neural tissue. Practically the vast majority are located in the abdomen, 90% of them in the adrenal medulla.

Pathophysiology

Catecholamines are synthesized in the adrenal medulla, in extraadrenal chromaffin cells, in the central nervous system, and in sympathetic nerve terminals. Embryologically, the adrenal medulla is derived from the undifferentiated sympathetic cells of the ectoderm, the sympathhogonia, which give rise to chromaffinoblasts and neuroblasts. The former constitute the pheochromocytes of the adrenal medulla and other chromaffin organs, while the latter form the cells of the sympathetic ganglia. Pheochromocytes, like other chromaffin cells, take on a brown color due to their adrenaline content in the presence of potassium dichromate, a characteristic that gave rise to the name of chromaffin organs.

The biosynthetic pathway of catecholamines begins with the amino acid tyrosine, which comes from food and the hepatic synthesis from phenylalanine. Tyrosine is hydroxylated, transforming into dihydroxyphenylalanine (DOPA), which by action of a decarboxylase is converted into dihydroxyphenylethylamine (dopamine). This gives rise to norepinephrine (NE) or norepinephrine. Its conversion to epinephrine (E) or epinephrine is mediated by a methylating enzyme found exclusively in the adrenal medulla and the organ of Zuckerkandl. Two enzyme systems are responsible for the inactivation of catecholamines. Circulating catecholamines are metabolized by catechol-O-methyltransferase (COMT), present in most tissues, which determines the short half-life of these compounds. The metabolites derived from the action of COMT are metanephrine and normetanephrine, the quantification of both being a useful index of total catecholamine production. Monoamine oxidase (MAO) is an enzyme located in nerve endings. A large proportion of the synthesized NE and E is deaminated prior to release. When catecholamines are metabolized by methylation and deamination, vanillin mandelic acid (AVM) is formed. Although its excretion does not reflect the physiological activity of catecholamines, it is an acceptable index of its total synthesis. Small amounts of NE and E are excreted unmetabolized in the urine.

Adrenergic effects have been divided into two types: alpha and beta, mediated through different receptors, the actions of catecholamines being determined by their ability to bind to these receptors. NE and E each have mixed alpha and beta effects, but NE is preferentially a stimulant of alpha receptors, whereas E is a stimulant of beta receptors. Stimulation of alpha receptors produces vasoconstriction, intestinal smooth muscle relaxation, sweat secretion, piloerection, mydriasis, and inhibition of insulin secretion. Stimulation of beta receptors causes vasodilation and relaxation of the intestinal and bronchial smooth muscles; increases heart rate and contraction and stimulates insulin release. Beta receptors are of two classes:

The hypersecretion of catecholamines, the relative proportion of NE and E, and the effects on the alpha and beta receptors of each of them (ability to bind to them) explain the clinical picture of pheochromacytoma.

Symptoms and signs

The clinical manifestations are multiple and variable. The symptoms, signs and complications that patients with a pheochromocytoma present are the consequence of the excessive concentration of catecholamines or the complications of arterial hypertension secondary to their pressor effects. The clinical expressions and findings can be paroxysmal or permanent.

The main symptom is high blood pressure. In approximately half of adults and in almost all children it is permanent. In the paroxysmal form, hypertensive attacks occur abruptly and can be triggered by multiple factors, such as change of position, physical or mental stress, physical activity, the Valsalva maneuver, and various surgical or diagnostic procedures. Characteristically, the attacks are accompanied by headache, tachycardia with palpitations, nausea or vomiting, paleness, tremor, anxiety, blurred vision, and a feeling of impending doom. There is a high incidence of orthostatic hypotension, which can be attributed to a defect in the peripheral vasomotor sympathetic reflexes (functional block induced by excessive levels of catecholamines), or to hypovolaemia as a consequence of chronic vasoconstriction. Rarely, a patient may present paradoxically with hypotension caused by a tumor that produces predominantly E, which is primarily a stimulant of vasodilation-producing beta receptors.

Catecholamine-induced cardiomyopathy can manifest clinically as tachyarrhythmias, non-specific electrocardiographic changes, and even frank heart failure. In patients with sustained hypertension, signs of retinopathy similar to those found in essential hypertension can be seen. As a consequence of the inhibition of insulin secretion and the stimulation of glycogenolysis, 40% of the patients develop overt diabetes or an intolerance to carbohydrates, which is evidenced in an oral glucide tolerance test. The manifestations that should lead to investigation of the existence of a pheochromocytoma are: paroxysmal or permanent hypertension with no apparent cause or that does not respond to adequate therapeutic measures,

Study methodology

Determination of urinary metanephrines . It is the most trustworthy method due to the low percentage of false negatives since its determination is less subject to interference by drugs and dietary factors compared to the other parameters that can be evaluated. In general, it is advisable to suspend for at least 72 hours and up to two weeks, if possible, hypotensive and vasoconstrictive drugs, sedatives, barbiturates, MAO inhibitors, as well as avoid the use of radiological contrast media containing methylglucamine , which interferes with laboratory reading. Normal values ​​are below 1 mg in 24-hour urine or 2 ng / mg of creatinine.

Measurement of urinary catecholamines . Under normal conditions they do not exceed 100 ug in 24-hour urine. When E constitutes more than 20% of the total catecholamines, it is probable that the pheochromocytoma is located in the adrenal medulla or in the organ of Zuckerkandl, the only organs where the methylating enzyme exists that transforms NE into E. They may exist, for action of various substances, false negatives (reserpine) or false positives (coffee, tea, L-dopa, quinidine, hydralazine, phenothiazines, aminophylline, etc.) Normal values ​​of AVM are below 6 mg in 24-hour urine ( Pisano's quantitative method), taking into consideration a series of substances that can give falsely positive or negative results.

Pharmacological tests . Due to the possibility of having methods for the quantification of catecholamines and their metabolites, pharmacological tests for diagnosis have limited utility, due to the risks involved and the high incidence of false positive and negative results.

Table 68.1. Effects induced by stimulation of alpha and beta receptors
  Alpha Beta
Vascular bed Vasoconstricción Vasodilation
Bronchial smooth muscle No action Relaxation
Intestinal smooth muscle Relaxation Relaxation
Cardiac inotropic effect No action Positive (stimulation)
Cardiac chronotropic effect No action Positive (stimulation)
Sweating Augmented No action
Pupils Mydriasis No action
Piloerección Yes No action
Insulin secretion Diminished Augmented

The clonidine test is based on the fact that normal central nervous system-mediated catecholamine release is suppressible by clonidine, a centrally acting alpha-adrenergic agonist, whereas autonomous tumor production of catecholamines is not. This test is advantageous in hypertensive patients, since it tends to lower blood pressure. Catecholamine plasma levels are determined before and at 60, 120 and 180 minutes after the administration of 100 to 300 ng of clonidine. In normal individuals, a fall in plasma catecholamines below 500 pg / ml is observed.

Imaging diagnosis . Once the diagnosis has been made by biochemical methods, the location of the pheochromocytoma is necessary, and it can be detected by nuclear magnetic resonance or computed axial tomography, as well as by a whole-body scintigraphy with a gamma camera using metaiodobenzylguanidine.