CASE 52 - Clinical Cases - Case Files Biochemistry, 3rd Edition (2015)

Case Files Biochemistry, 3rd Edition (2015)

SECTION II. Clinical Cases

CASE 52

A 35-year-old man presents with panic attacks, reporting that episodes of severe anxiety have been occurring for the last 4 months with increasing severity and duration. Along with the increased anxiety, he has experienced palpitations and headaches. Upon physical examination, he is found to be diaphoretic, his heart rate is 124 beats/minute, and blood pressure is 160/105 mm Hg. The heart rate is noted to be irregularly irregular. Electrocardiography (ECG) results show a rapid tachycardia without P waves. Elevated levels of catecholamines are present in the patient’s blood sample and a suprarenal mass is detected on the abdominal computed tomography scan.

image What is the most likely diagnosis?

image What is the mechanism of the patient’s symptoms?

ANSWERS TO CASE 52:

Pheochromocytoma

Summary: A 35-year-old man has anxiety, tachycardia, hypertension, elevated blood catecholamines and evidence of an adrenal mass. The examination and ECG findings reveal atrial fibrillation.

Most likely diagnosis: Pheochromocytoma

Mechanism of symptoms: Pheochromocytoma is a functional neoplasm arising from the adrenal medulla. It secretes the catecholamines epinephrine and norepinephrine in an unregulated manner. This increases the circulating levels of these hormones, which control heart rate, metabolism, and blood pressure. Symptoms are caused by the effects the increased hormone levels have on target tissues.

CLINICAL CORRELATION

Pheochromocytoma is a rare functional tumor, usually of the adrenal medulla, that has periodically increases the production of catecholamine. These tumors can occur sporadically or in some familial genetic syndromes (multiple endocrine neoplasia [MEN] type 2 and von Hippel-Lindau [VHL] syndrome). The classic clinical triad is headaches, sweating, and tachycardia. However, some patients do not present with this triad. Paroxysmal hypertension (periodic) is the most common sign, which occurs in 50% of patients with pheochromocytomas. The diagnosis is confirmed with either elevated serum metanephrines or elevated 24-hour urine levels of catecholamines and metanephrines. Computed tomography or magnetic resonance imaging can be used to identify the neoplasm. Most tumors (90%) occur in the adrenal gland; however, extramedullary neoplasms can arise from the inferior para-aortic region, bladder, thorax, and head/neck. Surgical excision of neoplasm is the treatment of choice but is a very high-risk procedure that requires careful monitoring and preoperative medication preparation to prevent a hypertensive crisis. Most neoplasms are benign (90%). Long-term follow-up is essential, as some “benign” tumors can reoccur several years later with distant metastasis. Meanwhile, the patient has significant dangers to his cardiovascular health, such as atrial fibrillation with rapid ventricular response and hypertension. The priorities regarding treatment of the atrial fibrillation include sympathetic blocking agents and ventricular rate control. A short-acting β-blocking agent such as esmolol would be helpful. A-adrenergic blocking agent such as phentolamine is effective to treat the hypertensive crisis.

APPROACH TO:

Pheochromocytoma

OBJECTIVES

1. Describe the normal regulation and secretion of catecholamines from the adrenal medulla.

2. Explain how catecholamines regulate metabolism, heart rate, and blood pressure.

3. Describe how the overproduction of catecholamines leads to the observed symptoms in the affected tissues and organs.

DEFINITIONS

AUTONOMIC NERVOUS SYSTEM: A part of the nervous system that regulates key involuntary functions of the body, including the activity of the heart muscle, the smooth muscles, including the muscles of the intestinal tract, and the glands. The autonomic nervous system has 2 divisions: (1) the sympathetic nervous system, which accelerates the heart rate, constricts blood vessels, and raises blood pressure, and (2) the parasympathetic nervous system, which slows the heart rate, increases intestinal and gland activity, and relaxes the sphincter muscles.

CATECHOLAMINES: An amine derived from the amino acid tyrosine, including epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine, which act as hormones or neurotransmitters.

FUNCTIONAL NEOPLASM: A hormone-secreting tumor in an endocrine gland.

GERMLINE MUTATION: A gene change in a body’s reproductive cell (egg or sperm) that becomes incorporated into the DNA of every cell in the body of the offspring. Germline mutations are passed on from parents to offspring.

PREGANGLIONIC NEURONS: A preganglionic neuron cell body is located within the central nervous system (brain stem or spinal cord). They send fibers out the ventral root and leave the spinal nerves through the white rami (myelin), entering the sympathetic trunk.

SECOND MESSENGERS: Molecules inside cells that act to transmit signals from a receptor to a downstream target.

DISCUSSION

Pheochromocytomas are tumors of the adrenal gland, arising from chromaffin cells that synthesize, store, metabolize, and secrete catecholamines. The majority is benign with an incidence of malignancy commonly reported to be 10%, although they carry a high risk of morbidity and mortality from cardiovascular complications. The normal age of presentation is early to mid-adulthood, although tumors may occur at any age. Normally, the adrenal medulla secretes hormones in response to stimulation by the sympathetic division of the autonomic nervous system. However, in the case of pheochromocytoma, catecholamine secretion becomes unregulated and excessive amounts are present in the blood stream. The resulting symptoms produced by such neoplasms directly relate to the effects of catecholamines on target tissues and include abdominal pain, chest pain, irritability, nervousness, pallor, palpitations, rapid heart rate, severe headaches, sweating, weight loss, hand tremor, high blood pressure, and difficulty sleeping.

Although most cases of pheochromocytoma are sporadic, a significant proportion have been linked to mutations in several genes known to cause various syndromes: VHL disease due to mutations of the VHL gene, MEN types 2A and 2B due to germline mutations of the RET gene, neurofibromatosis type 1 due to mutations of the NF gene, and pheochromocytoma syndromes caused by mutations of genes for members of the succinate dehydrogenase family (SDHB, SDHC, and SDHD). The proportion of pheochromocytoma cases due to these mutations has been reported to be as low as 10% and as high as 24%. Of these cases, germline mutations occurred most frequently in the VHL gene followed by RET, SDHB, and SDHD genes.

Normally, when the body is stressed, for example, during exercise or a fear response, nerve impulses from the hypothalamus stimulate sympathetic preganglionic neurons. The inner region (medulla) of the adrenal gland is a modified sympathetic ganglion of the autonomic nervous system. Although it arises from the same embryonic tissue as other sympathetic ganglia, its cells do not have axons and form clusters around blood vessels. When these cells (chromaffin cells) are stimulated by action potentials from sympathetic preganglionic neurons in the splanchnic nerve, they secrete the catecholamines epinephrine and norepinephrine. Catecholamines are synthesized from tyrosine, as depicted in Figure 52.1. These hormones augment the “fight-or-flight” response by increasing heart rate and the force of contraction, thereby increasing cardiac output and blood pressure. Simultaneously, the catecholamines dilate airways in the lungs, increase blood glucose and fatty acid concentrations to boost energy supplies, and increase blood flow to the heart, liver, skeletal muscles, and adipose tissue.

image

Figure 52-1. Biosynthesis of the catecholamines norepinephrine and epinephrine from the amino acid tyrosine.

Epinephrine can exert its effect on target tissues by binding to two distinct types of G-protein coupled receptors, the β-adrenergic receptor or the α2-adrenergic receptor. These receptors are coupled to different intracellular G proteins. Both β1- and β2-adrenergic receptors are coupled to Gs proteins, which activate adenylyl cyclase. In contrast, α1 and α2 receptors are coupled to two other G proteins, Gq and Gi, respectively. Gi inhibits adenylyl cyclase, and Gq stimulates phospholipase C to generate inositol triphosphate and diacyl glycerol, which act as second messengers in intracellular signaling pathways.

During periods of physiologic stress, all tissues have an increased need for glucose and fatty acids. These fuels can be supplied to the blood in seconds by the rapid breakdown of glycogen in the liver (glycogenolysis) and of triacylglycerol in the adipose storage cells (lipolysis). Both adipocytes and hepatocytes contain β-adrenergic receptors that, when epinephrine binds, trigger the liberation of glucose and fatty acids through the above mentioned signaling pathways. Epinephrine also binds to similar β-adrenergic receptors on cardiac muscle cells to increase the contraction rate, thereby increasing blood supply to the tissues. Epinephrine bound to β-adrenergic receptors on smooth muscle cells of the intestine causes them to relax. The α2-adrenergic receptor is present on smooth muscle cells lining the blood vessels in the intestinal tract, skin, and kidneys. Epinephrine bound to α2 receptors causes the arteries to constrict, reducing circulation to these peripheral organs. Although the effects of epinephrine are diverse, they are each directed to supplying energy for the rapid movement of major locomotor muscles in response to bodily stress.

Pheochromocytoma treatment most often involves surgical removal of the tumor. In addition, blood pressure and pulse must be stabilized with medication before surgery. When the tumor cannot be surgically removed, medication is utilized to manage the resulting symptoms. This is typically a combinatorial approach of medications to control the effects of the excessive amounts of circulating hormones. As most of the pheochromocytomas are benign, radiation therapy and chemotherapy have not been effective in curing this kind of tumor.

COMPREHENSION QUESTIONS

52.1 Catecholamine secretion from a pheochromocytoma is considered unregulated. This is because the tumor:

A. Lacks β-adrenergic receptors

B. Contains defective transport molecules

C. Is not innervated

D. Lacks α-adrenergic receptors

52.2 Which of the following is not a tissue response of increased catecholamine secretion?

A. Constriction of airways

B. Hepatic conversion of glycogen to glucose

C. Increased heart rate

D. Dilation of blood vessels of skeletal muscle

52.3 Despite recommended preoperative preparation with α- and β-adrenergic blockers, severe hemodynamic instability may occur during operations to resect pheochromocytoma. Some preoperative protocols recommend the addition of the tyrosine hydroxylase inhibitor, metyrosine, in an attempt to better manage the hypertension of patients with pheochromocytoma undergoing surgical resection. What mechanism does this treatment utilize to control hemodynamic stability?

A. Catecholamine metabolism

B. Catecholamine synthesis

C. Catecholamine-receptor binding

D. Catecholamine secretion

ANSWERS

52.1 C. Normally, catecholamine secretion is regulated by the hypothalamus through innervation of the adrenal medulla via sympathetic preganglionic neurons. A pheochromocytoma lacks this innervation and, thus, the normal regulatory mechanisms.

52.2 A. Catecholamine secretion enhances the “fight-or-flight response.” Therefore, the complementary actions of target tissue are aimed at increasing blood flow, energy supplies in the form of glucose, and oxygen to skeletal muscles. The airways dilate rather than constrict to accomplish this goal.

52.3 B. Metyrosine is an inhibitor of the enzyme tyrosine 3-monooxygenase, and consequently of the synthesis of catecholamines. It is used to control the symptoms of excessive sympathetic stimulation in patients with pheochromocytoma.

BIOCHEMISTRY PEARLS

image Pheochromocytomas are classified as functional neoplasms that secrete the catecholamines norepinephrine and epinephrine.

image Catecholamines function by signaling through G-protein coupled receptors on target tissues.

image Normal hypothalamic regulation of catecholamine release from the adrenal medulla is compromised by the hypersecretion of these hormones from the tumor.

REFERENCES

Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet. 2012;205(1-2):1-11.

Goldstein RE, O’Neill JA Jr, et al, Clinical experience over 48 years with pheochromocytoma. 1999. Ann Surg. 1999;229:755-766.

Lodish H, Berk A, Zipursky SL, et al. G Protein–Coupled Receptors and Their Effectors. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000: Sec 20.3.

Tortura GJ and Derrickson B. The Endocrine System. Principles of Anatomy and Physiology. 11th edition. New Jersey: John Wiley & Sons; 2007: Chap 18.

Voet D, Voet JG. Signal transduction-hormones. Biochemistry. 3rd ed. Hoboken, NJ: John Wiley & Sons, Inc; 2004.

Young W, Kaplan N, Lacroix A, Martin K. Clinical presentation and diagnosis of pheochromocytoma. www.uptodate.com.