Pheochromocytoma Workup

A pheochromocytoma is a catecholamine-secreting tumor that arises from the chromatin cells of the adrenal medulla. Extraadrenal pheochromocytoma arise from the sympathetic ganglia and are referred to as catecholamine-secreting paragangliomas. These neoplasms are very rare, occurring in less than 0.2% of the patients. Most catecholamine-secreting tumors are sporadic and occur in the fourth to fifth decade of life, effecting both men and women equally. However, about 40% of the patients that present with a pheochromocytoma there is a familial inheritance. These familial tumors arise earlier in life and typically associated with several familial disorders. Such disorders are Von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN2), and neurofibromatosis (NF1).

Clinical Presentation

Symptoms and signs only occur in about 50% of patients and paroxysmal in nature. There is a classic triad of symptoms that is observed which consists of episodic headache, sweating, and tachycardia with either paroxysmal hypertension or primary hypertension. Paroxysmal hypertension is the most common sign of pheochromocytoma. The headache associated with pheochromocytoma can vary from mild to severe and occurs in 90% of patients. Generalized sweating occurs accompanied by forceful palpitations, tremors, dyspnea, fatigue, and often anxiety and panic attack-type symptoms. There is increased secretion of catecholamines; epinephrine, norepinephrine, and dopamine which cause abnormalities in carbohydrate metabolism which leads to insulin resistance, and an impaired fasting glucose which mimics type 2 diabetes mellitus. In rare cases there is episodic hypotension and rapid cyclic fluctuations of hypertension and hypotension.

Initial Evaluation

The diagnosis of pheochromocytoma is made upon biochemical testing for catecholamine hypersecretion, followed by imaging studies to identify an adrenal tumor. There are many indications for testing that a physician may take into consideration before subjecting patients to many tests and appointments. Some of the indications for testing include the classic triad of symptoms (headache, sweating, and tachycardia), hyperadrenergic spells (palpitations, diaphoresis, tremor, pallor), onset of paroxysmal hypertension or primary hypertension at an early age, or any familial syndromes or history of pheochromocytoma.

Biochemical Testing

The range of biochemical testing that is performed is based upon the index of suspicion that the patient in fact has a pheochromocytoma. Low index of suspicion includes a 24-hour urinary fractionated catecholamines and metanephrines. If there is a high index of suspicion, it is recommended to use a plasma fractionated metanephrines. These tests are performed by high-performance liquid chromatography (HPLC) with tandem mass spectroscopy or electrochemical detection. The more recent techniques have overcome the traditional problems that are associated with drug interference and contrast agents.

Catecholamines

Catecholamines are an organic compound that are derived from the amino acid tyrosine. Tyrosine can either be derived from diet or synthesized from phenylalanine. Epinephrine, norepinephrine, and dopamine are the primary catecholamines that are secreted from the adrenal medulla during the sympathetic flight-or-fight response.

Norepinephrine is a neuromodulator and a hormone that circulates in the blood. Its primary function is to mobilize the brain and the body for action as part of the peripheral sympathetic system. In the flight-or-fight response norepinephrine causes arousal and alertness. It enhances the formation and retrieval of memory, and focuses attention. As a hormone it increases cardiac output by increasing the heart rate and blood pressure. It triggers glycolysis and increases vascular blood flow to the skeletal muscles.

Dopamine functions as a neurotransmitter that is released by neurons to send signals to other functioning nerve synapses. Dopamine plays a critical role in reward-motivated behavior. The anticipation of most types of rewards increase the levels of dopamine in the brain. Many addictive drugs mimic this pathway while simultaneously blocking the reuptake of it. Dopamine is also functional in the motor control pathway as a neuromodulator which controls the release of many other hormones. In circulation outside of the brain, dopamine functions as a chemical messenger. It inhibits norepinephrine release and acts as a vasodilator. It increases renal excretion of sodium. It acts to reduce insulin secretion and gastrointestinal motility.

Epinephrine, also known as adrenaline or adrenalin functions as a neurotransmitter, hormone, and as a medication. It plays an important role in increasing cardiac output, pupil dilation, and increasing insulin release to stimulate glycolysis. It acts on the alpha and beta receptors to ultimate activate the flight-or-fight response. Epinephrine is also used medically to treat a number of conditions including anaphylaxis, cardiac arrest, and bleeding.

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Glycolysis

Glycolysis is the first phase of a series of reactions for the catabolism of carbohydrates. Catabolism is the breakdown of larger molecules into its respective smaller constituents. Glycolysis is the first part of cellular respiration that generates pyruvate to be used in either anaerobic respiration in the absence of oxygen or in the TCA cycle in aerobic respiration which yields useable energy for cells. This will be a general outline of the steps in glycolysis.

The whole process can be broken down into an energy investment phase where ATP is being used and an energy payoff phase where ATP is being generated. Fructose-1,6-biphosphate is where the energy investment phase ends. That is where the last ATP has to be used for energy to drive glycolysis.

A simple equation can be remembered as a summary of glycolysis.

Glucose + 2 ADP + 2 phosphate ions + 2 NAD+ —-> 2 Pyruvate + 2 ATP + 2 NADH + 2 H20 + 2 H+.

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In the first step of glycolysis an addition of a high energy phosphate from ATP yields glucose-6-phosphate and ADP. This step is initialized by the enzyme hexokinase. G6P is more reactive than glucose.

In the next step, glucose-6-phosphate is converted to its isomer, fructose-6-phosphate by phosphoglucose isomerase.

In the third step of glycolysis, fructose-6-phosphate is converted to fructose-1,6-biphosphate by phosphofructokinase (PFK) and the addition of ATP. This is the committed step, meaning that fructose-1,6-biphosphate MUST be converted to pyruvate. This is also the end of the energy investment phase of glycolysis.

Fructose-1,6-biphosphate is converted to glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate catalyzed by aldolase. Glyceraldehyde-3 phosphate maintains a reversible reaction with dihydroxyacetone phosphate through triode phosphate isomerase. The resulting reaction generates two molecules of glyceraldehyde-3-phosphate. A key point going forward is that two molecules of each substrate are produced.

Each G3P molecule gains an inorganic phosphate and with the addition of NAD+ to form the energized carrier molecules NADH. The resulting reaction catalyzed by glyeraldehyde-3-phosphate dehydrogenase generates two molecules of 1,3-bisphophoglycerate which yield two high energy phosphates.

Through the addition of two low energy ADP molecules and the enzyme phosphoglycerate kinase, the two molecules of 1,3-bisphophoglycerate are converted to 3-phosphoglycerate and yields two molecules of ATP. This reaction is called the break even reaction because at this point the energy input is equal to the energy output. Two molecules of ATP were expended and at this step there was a generation of two ATP molecules.

In the next step the two molecules of 3-phosphoglyercate are converted to 2-phosphoglycerate through the enzymatic properties of phosphoglycerate mutase.

The molecules of 2-phosphoglycerate are converted to phosphoenolpyruvate catalyzed by enolase. This step yields H20 molecules.

In the final step of glycolysis, the molecules of phosphoenolpyruvate are converted to pyruvate catalyzed by pyruvate kinase. ATP is generated from the addition of ADP and the two high energy phosphates from the molecules of phosphoenolpyruvate.

Upon the completion of glycolysis, the pyruvate molecules can be oxidized to carbon dioxide in cellular respiration to generate 28 molecules of ATP.

The NADH that is produced is turned back into NAD+ to drive further glycolysis. There are two ways to accomplish this. In the presence of oxygen NADH passes it electrons into the electron transport chain, which regenerates NAD+ for use in glycolysis. In the absence of oxygen, cells regenerate NAD+ by undergoing fermentation.