# Lecture 9: Adrenal Medulla and Pheochromocytoma ## Unit 2.3: Endocrine System --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Describe the anatomy and embryology of the adrenal medulla 2. Explain catecholamine synthesis, storage, and secretion 3. Describe the physiologic actions of catecholamines 4. Explain the pathophysiology and clinical features of pheochromocytoma 5. Describe the diagnostic workup for pheochromocytoma 6. Explain the management and genetic syndromes associated with pheochromocytoma --- ## Lecture Outline ### I. Adrenal Medulla Anatomy The adrenal medulla is functionally a modified sympathetic ganglion, sharing embryologic origin with sympathetic nervous tissue. Understanding its unique anatomy and relationship to the adrenal cortex explains its specialized function and the clinical presentation of medullary tumors. The structure of the adrenal medulla positions it at the center of the adrenal gland. It comprises approximately 10-20% of total adrenal mass, with the cortex forming the outer 80-90%. The medulla derives from neural crest cells (neuroectoderm), the same embryologic origin as sympathetic ganglia throughout the body. The functional cells are chromaffin cells, named for their characteristic brown staining with chromium salts due to oxidation of stored catecholamines. Unlike typical postganglionic sympathetic neurons, chromaffin cells release their catecholamines directly into the bloodstream rather than at synaptic junctions, functioning as neuroendocrine cells. The blood supply to the adrenal medulla has important physiologic implications. The arterial supply is shared with the cortex, deriving from superior, middle, and inferior adrenal arteries. A unique portal system exists whereby cortical blood drains through the medulla before entering the central vein. This arrangement exposes medullary chromaffin cells to cortisol concentrations 100-fold higher than systemic levels. This cortisol-rich blood induces phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. Venous drainage is asymmetric: the right adrenal vein enters directly into the inferior vena cava (short, making catheterization difficult), while the left adrenal vein enters the left renal vein (longer, more accessible). The innervation of the adrenal medulla reflects its nature as a modified sympathetic ganglion. Preganglionic sympathetic fibers from the thoracic spinal cord (T5-T11) travel through the splanchnic nerves to synapse directly on chromaffin cells. The neurotransmitter at these synapses is acetylcholine, acting on nicotinic receptors on chromaffin cells. This means the medulla effectively serves as the postganglionic neuron equivalent, but instead of releasing norepinephrine onto a target organ, it releases catecholamines into the systemic circulation for widespread hormonal effects. Panel A: Cross-section of the adrenal gland with central medulla (10-20%) and outer cortex (80-90%) clearly demarcated with distinct coloring for each region. Panel B: Embryologic origin inset comparing neural crest cell development into both sympathetic ganglia and adrenal medulla chromaffin cells as parallel differentiation pathways. Panel C: Portal blood supply system illustration showing cortical blood rich in cortisol draining through the medulla, with annotation of cortisol inducing PNMT enzyme expression in chromaffin cells. Panel D: Innervation diagram showing preganglionic sympathetic fibers from spinal cord T5-T11 traveling via splanchnic nerves to synapse directly on chromaffin cells with acetylcholine at nicotinic receptors. --- ### II. Chromaffin Cells Chromaffin cells are the specialized neuroendocrine cells of the adrenal medulla, named for their characteristic histochemical staining. Understanding their structure and distribution throughout the body informs both normal physiology and the clinical presentation of catecholamine-secreting tumors. The characteristics of chromaffin cells reflect their specialized secretory function. The name derives from their brown coloration when exposed to chromium salts (chromaffin reaction), caused by oxidation of catecholamines within secretory granules. These dense-core vesicles (chromaffin granules) store catecholamines along with ATP and chromogranins. Two populations exist in the adrenal medulla: approximately 80% produce primarily epinephrine, while 20% produce primarily norepinephrine. The predominance of epinephrine-secreting cells reflects the high local cortisol concentrations that induce PNMT. The cellular organization of chromaffin cells facilitates rapid hormone release. Cells are arranged in clusters and cords, surrounded by fenestrated capillaries that allow efficient hormone release into the circulation. Dense sympathetic nerve terminals provide the regulatory input, with each nerve fiber innervating multiple chromaffin cells. Paraganglia represent extra-adrenal collections of chromaffin tissue distributed throughout the body. The organ of Zuckerkandl is a para-aortic body located near the origin of the inferior mesenteric artery; it is prominent in fetal life and regresses postnatally but can give rise to extra-adrenal pheochromocytomas (paragangliomas). Paraganglia in the bladder wall can cause catecholamine release with micturition, producing symptoms of hypertension and palpitations during urination. The carotid body and aortic bodies function as chemoreceptors for oxygen and pH. Other paraganglia are distributed throughout the thorax, pelvis, and head/neck region. Tumors arising from extra-adrenal chromaffin tissue are termed paragangliomas and have higher rates of malignancy than adrenal pheochromocytomas. Panel A: Ultrastructural features of a chromaffin cell showing dense-core secretory granules containing catecholamines, ATP, and chromogranins with surrounding fenestrated capillaries for hormone release. Panel B: Sympathetic nerve terminal synapsing on chromaffin cell with acetylcholine at nicotinic receptors, showing calcium influx and exocytosis mechanism for catecholamine release. Panel C: Body diagram showing distribution of paraganglia including organ of Zuckerkandl (para-aortic near inferior mesenteric artery), bladder wall, carotid and aortic bodies, and thoracic and head/neck locations. Panel D: Chromaffin reaction illustration showing cells staining brown when exposed to chromium salts due to oxidation of stored catecholamines, with annotation of the two chromaffin cell populations (80% epinephrine, 20% norepinephrine). --- ### III. Catecholamine Synthesis The biosynthesis of catecholamines proceeds through a well-characterized enzymatic pathway beginning with the amino acid tyrosine. Understanding each step explains the pharmacologic targets for treating catecholamine excess and the significance of cortisol in determining the medulla's hormonal output. The synthetic pathway proceeds through four enzymatic steps. Tyrosine hydroxylase converts tyrosine to L-DOPA (L-3,4-dihydroxyphenylalanine) and represents the rate-limiting step in catecholamine synthesis. This enzyme is subject to feedback inhibition by dopamine and norepinephrine. DOPA decarboxylase (aromatic L-amino acid decarboxylase) converts L-DOPA to dopamine; this reaction requires pyridoxal phosphate (vitamin B6) as a cofactor. Dopamine β-hydroxylase (DBH) converts dopamine to norepinephrine; this reaction occurs within secretory vesicles (after dopamine is transported in) and requires vitamin C as a cofactor. DBH is released along with catecholamines during exocytosis and can be measured in plasma. Phenylethanolamine N-methyltransferase (PNMT) converts norepinephrine to epinephrine; this reaction occurs in the cytoplasm, so norepinephrine must exit the vesicle, be methylated, and reenter a vesicle for storage. The critical role of PNMT and cortisol explains why the adrenal medulla is the primary source of circulating epinephrine. PNMT requires induction by high cortisol concentrations—concentrations achieved only through the portal blood supply from the cortex. This anatomic arrangement means that only adrenal medullary chromaffin cells produce significant amounts of epinephrine. Extra-adrenal paraganglia, lacking this cortisol exposure, produce primarily norepinephrine and dopamine. In conditions of cortisol deficiency, or in paragangliomas, norepinephrine rather than epinephrine predominates. Storage of catecholamines occurs in dense-core vesicles (chromaffin granules). These granules contain extremely high concentrations of catecholamines (approximately 0.5 M), maintained by vesicular monoamine transporters and stabilized by complexing with ATP and chromogranins. Chromogranin A is the most abundant granin protein and is co-released with catecholamines; it serves as a tumor marker for pheochromocytoma and other neuroendocrine tumors. Panel A: Sequential enzymatic steps of catecholamine synthesis showing tyrosine to L-DOPA (tyrosine hydroxylase, rate-limiting with feedback inhibition), L-DOPA to dopamine (DOPA decarboxylase, vitamin B6 cofactor), dopamine to norepinephrine (DBH, vitamin C, occurs in vesicle), and norepinephrine to epinephrine (PNMT, cytoplasmic, cortisol-induced). Panel B: Vesicular compartmentalization showing dopamine transported into secretory vesicle, converted to norepinephrine inside the vesicle, norepinephrine exiting for cytoplasmic methylation to epinephrine, and epinephrine reentering vesicle for storage. Panel C: Cortisol portal system diagram showing cortex-to-medulla blood flow delivering cortisol concentrations 100-fold higher than systemic levels to induce PNMT enzyme expression in chromaffin cells. Panel D: Chromaffin granule contents showing stored catecholamines at approximately 0.5 M concentration complexed with ATP and chromogranin A, with vesicular monoamine transporters labeled. --- ### IV. Catecholamine Secretion and Metabolism Catecholamine secretion from chromaffin cells follows a classic stimulus-secretion coupling mechanism, while metabolism through specific enzymatic pathways generates the metabolites used for diagnostic testing. Understanding these pathways informs both physiologic responses and laboratory evaluation of suspected pheochromocytoma. The secretion mechanism involves stimulus-secretion coupling. Sympathetic activation leads to acetylcholine release at preganglionic terminals, activating nicotinic receptors on chromaffin cells. Nicotinic receptor activation causes calcium influx through voltage-gated calcium channels. The resulting increase in intracellular calcium triggers exocytosis of chromaffin granules, releasing their entire contents: catecholamines, ATP, and chromogranins. Physiologic stimuli for secretion include stress, exercise, hypoglycemia, and any condition activating the sympathetic nervous system. Circulating catecholamine levels reflect their different sources. Epinephrine in the circulation derives almost exclusively from the adrenal medulla (approximately 99%), with minimal contribution from sympathetic nerves. Normal plasma epinephrine is approximately 25-50 pg/mL. Norepinephrine derives primarily from sympathetic nerve terminals (approximately 80%) with the adrenal medulla contributing approximately 20%. Normal plasma norepinephrine is 100-400 pg/mL. Dopamine circulates at low levels, primarily from sympathetic nerves. Catecholamine metabolism proceeds through two enzyme systems. Catechol-O-methyltransferase (COMT) is located in extraneuronal tissues (including the adrenal medulla itself, liver, and kidney) and catalyzes O-methylation of the catechol ring. Monoamine oxidase (MAO) is located in neuronal mitochondria and catalyzes oxidative deamination. Sequential action of these enzymes generates the final metabolites. The primary metabolites with diagnostic significance include metanephrine (from epinephrine, via COMT), normetanephrine (from norepinephrine, via COMT), and vanillylmandelic acid (VMA, the final urinary metabolite from both). Homovanillic acid (HVA) is the dopamine metabolite and serves as a marker for neuroblastoma. Plasma free metanephrines (metanephrine and normetanephrine) have become the preferred diagnostic test for pheochromocytoma. These metabolites are produced continuously within adrenal chromaffin cells by COMT acting on catecholamines leaking from storage vesicles. Unlike catecholamines, which are released episodically, metanephrines provide a more stable marker of catecholamine production. This explains why plasma free metanephrines have the highest sensitivity for detecting pheochromocytoma. Panel A: Secretion mechanism showing preganglionic acetylcholine binding nicotinic receptors, calcium influx through voltage-gated channels, and vesicle exocytosis releasing catecholamines, ATP, and chromogranins into fenestrated capillaries. Panel B: Metabolic pathways showing catecholamines metabolized by COMT (extraneuronal, O-methylation) and MAO (neuronal, oxidative deamination) with products metanephrine, normetanephrine, VMA, and HVA labeled with enzyme locations. Panel C: Normal plasma catecholamine concentrations showing epinephrine (25-50 pg/mL, 99% from adrenal medulla), norepinephrine (100-400 pg/mL, 80% from sympathetic nerves), and dopamine at low levels. Panel D: Rationale for plasma free metanephrines as preferred diagnostic markers showing continuous intracellular production from COMT acting on catecholamines leaking from storage vesicles, providing stable measurement independent of episodic secretion. --- ### V. Catecholamine Receptors and Actions Catecholamines exert their effects through adrenergic receptors, a family of G protein-coupled receptors with distinct tissue distributions and physiologic effects. Understanding receptor pharmacology explains both the clinical manifestations of catecholamine excess and the principles of medical treatment. Adrenergic receptors are classified into α and β subtypes with distinct signaling pathways. α₁ receptors couple to Gq proteins, activating phospholipase C to generate IP3 (releasing calcium from internal stores) and diacylglycerol (activating protein kinase C). α₁ receptors are located primarily on vascular smooth muscle, where activation causes vasoconstriction. α₂ receptors couple to Gi proteins, decreasing cAMP. Presynaptic α₂ receptors provide negative feedback on norepinephrine release; α₂ receptors in the pancreas inhibit insulin secretion. β₁ receptors couple to Gs proteins, increasing cAMP, and are located primarily in the heart, where activation increases heart rate and contractility. β₂ receptors also couple to Gs, and are found in bronchial smooth muscle (causing bronchodilation), blood vessels (causing vasodilation, particularly in skeletal muscle), and uterus (causing relaxation). β₃ receptors in adipose tissue mediate lipolysis. Receptor affinity differs between catecholamines and explains their distinct effects. Norepinephrine has high affinity for α₁, α₂, and β₁ receptors but much lower affinity for β₂. This explains why norepinephrine causes predominantly vasoconstriction (α₁) with modest cardiac stimulation (β₁) but little vasodilation or bronchodilation (β₂). Epinephrine has relatively equal affinity for all receptor subtypes, producing more balanced effects including both vasoconstriction (α) and vasodilation (β₂), along with cardiac stimulation (β₁). Cardiovascular effects of catecholamines dominate the clinical picture in pheochromocytoma. β₁ stimulation in the heart increases rate (chronotropy) and contractility (inotropy). α₁ stimulation causes vasoconstriction and increased systemic vascular resistance. β₂ stimulation in skeletal muscle vasculature causes vasodilation. The net blood pressure effect depends on the balance of these effects and the predominant catecholamine. Metabolic effects reflect catecholamines' role in mobilizing energy substrates. Glycogenolysis is stimulated in both liver (β₂) and muscle (α₁), increasing blood glucose. Gluconeogenesis is enhanced via α and β effects. Lipolysis in adipose tissue is stimulated via β₃ receptors, increasing free fatty acids. Insulin secretion is inhibited via α₂ receptors in pancreatic β cells, contributing to hyperglycemia. Glucagon secretion is stimulated via β₂ receptors. Other catecholamine effects occur throughout the body. β₂ stimulation causes bronchodilation, exploited therapeutically with β₂ agonists for asthma. Gastrointestinal motility is decreased while sphincter tone increases. Bladder smooth muscle relaxes (β₂) while the sphincter contracts (α₁). Pupillary dilation (mydriasis) occurs via α₁ activation of the dilator pupillae. Uterine relaxation (β₂) is the basis for tocolytic therapy. Panel A: Adrenergic receptor classification with signaling pathways showing alpha-1 (Gq to IP3 and calcium), alpha-2 (Gi to decreased cAMP), and beta-1, beta-2, beta-3 (Gs to increased cAMP) with second messenger cascades illustrated. Panel B: Body diagram showing receptor distribution and effects by organ including heart (beta-1 for rate and contractility), blood vessels (alpha-1 for vasoconstriction, beta-2 for vasodilation), bronchi (beta-2 for dilation), pancreas (alpha-2 for decreased insulin), and adipose (beta-3 for lipolysis). Panel C: Relative receptor affinities comparing norepinephrine (high for alpha-1, alpha-2, and beta-1 but low for beta-2) versus epinephrine (relatively equal affinity for all subtypes) with clinical effect implications. Panel D: Metabolic effects summary showing glycogenolysis (beta-2 liver, alpha-1 muscle), gluconeogenesis enhancement, lipolysis (beta-3), insulin inhibition (alpha-2), and glucagon stimulation (beta-2) during catecholamine activation. --- ### VI. Pheochromocytoma - Overview Pheochromocytoma is a catecholamine-secreting tumor arising from chromaffin cells, most commonly in the adrenal medulla. While traditionally characterized by the "rule of 10s," current understanding recognizes significantly higher rates of hereditary disease. Recognition and appropriate treatment are essential, as undiagnosed pheochromocytoma carries substantial morbidity and mortality. The definition and epidemiology of pheochromocytoma establish its clinical significance. Pheochromocytoma refers to catecholamine-secreting tumors arising from adrenal medullary chromaffin cells. Extra-adrenal tumors arising from paraganglia are termed paragangliomas; together these are often called pheochromocytoma/paraganglioma (PPGL). Approximately 80-85% arise in the adrenal medulla, with 15-20% extra-adrenal. Incidence is approximately 2-8 per million per year. Pheochromocytoma is found in approximately 0.1-0.5% of hypertensive patients. The traditional "rule of 10s" has been revised based on improved understanding. This mnemonic stated that approximately 10% of pheochromocytomas were bilateral, 10% malignant, 10% extra-adrenal, 10% familial, and 10% pediatric. Current evidence has substantially revised these estimates. Hereditary cases are now recognized in 30-40% of patients—far higher than the traditional 10%—driving the recommendation for genetic testing in all patients. Malignancy rates of 10-15% remain accurate overall but are much higher (30-40%) in patients with SDHB mutations. Bilateral tumors are common in hereditary syndromes, particularly VHL and MEN2. Clinical presentation is dominated by hypertension, typically accompanied by the classic triad. Hypertension is present in 90-95% of patients. The classic triad comprises episodic headache (80% of patients), diaphoresis (70%), and palpitations (60%). These symptoms occurring together with hypertension are highly suggestive of pheochromocytoma. Hypertension patterns vary among patients. Sustained hypertension occurs in approximately 50% of patients, sometimes difficult to distinguish from essential hypertension. Paroxysmal hypertension with episodes superimposed on normal or elevated baseline pressure occurs in approximately 45%. Approximately 5% remain normotensive between episodes. Paradoxically, orthostatic hypotension may occur due to volume depletion from chronic catecholamine-induced vasoconstriction and natriuresis. Panel A: Anatomic locations showing adrenal medulla origin (80-85%) versus extra-adrenal paraganglia sites (15-20%) including organ of Zuckerkandl, bladder wall, and other thoracic and head/neck locations on a body diagram. Panel B: Classic triad of pheochromocytoma showing episodic headache (80%), diaphoresis (70%), and palpitations (60%) occurring together with hypertension (present in 90-95% of patients). Panel C: Hypertension patterns showing sustained hypertension (50%), paroxysmal hypertension (45%), and normotensive between episodes (5%), with orthostatic hypotension paradox explained by chronic volume depletion. Panel D: Comparison of traditional rule of 10s with updated understanding emphasizing hereditary cases now recognized at 30-40% (not 10%), genetic testing recommended for all patients, and malignancy rates of 10-15% overall but 30-40% in SDHB mutation carriers. --- ### VII. Pheochromocytoma - Clinical Features The clinical manifestations of pheochromocytoma result from episodic or sustained catecholamine excess. Recognizing the varied presentations, potential triggers, and complications enables appropriate diagnostic consideration and prevents potentially fatal outcomes. Paroxysms are the hallmark of pheochromocytoma, though not all patients experience them. Episodes typically last minutes to hours, varying in frequency from multiple daily to monthly or less. Symptoms during paroxysms include severe headache (often pounding), profuse sweating, palpitations, tremor, and a sense of impending doom or anxiety. Pallor rather than flushing occurs due to catecholamine-induced vasoconstriction. Paroxysms may occur spontaneously or be triggered by specific precipitants. Triggers for catecholamine release include physical factors such as exercise, straining (Valsalva), abdominal palpation, or changes in body position. Certain medications can precipitate crises: opioids (particularly during anesthesia induction), metoclopramide (via dopamine receptor blockade), glucagon, and tyramine-containing foods (in MAO inhibitor users). Anesthetic induction agents and intubation are particularly dangerous triggers in undiagnosed patients. Tumor manipulation during surgery can cause massive catecholamine release, explaining the need for careful preoperative preparation. Cardiovascular complications represent the major source of morbidity and mortality. Hypertensive crisis can be life-threatening. Catecholamine-induced cardiomyopathy (similar to Takotsubo or stress cardiomyopathy) results from direct catecholamine toxicity and can cause heart failure. Arrhythmias including tachyarrhythmias and, less commonly, bradycardia may occur. Myocardial infarction can result from demand ischemia (increased myocardial oxygen demand exceeding supply) even in the absence of coronary artery disease. Stroke may result from hypertensive crisis. Metabolic features reflect catecholamine effects on glucose and fat metabolism. Hyperglycemia occurs due to α₂-mediated inhibition of insulin secretion combined with enhanced glycogenolysis and gluconeogenesis. Weight loss commonly occurs despite adequate caloric intake, reflecting the increased metabolic rate. Some tumors produce PTH-related peptide (PTHrP) causing hypercalcemia. Erythrocytosis occasionally occurs from erythropoietin production. Other clinical features include pallor (from vasoconstriction—notably NOT flushing), anxiety and panic attacks, constipation from decreased gastrointestinal motility, and fine tremor from β-adrenergic activation. Panel A: Typical paroxysm timeline showing symptom onset, peak lasting minutes to hours, and resolution with associated symptoms including severe headache, profuse sweating, palpitations, pallor (not flushing), and sense of impending doom. Panel B: Precipitants organized by category showing physical triggers (exercise, straining, position changes), medications to avoid with warning symbols (opioids, metoclopramide, glucagon), and surgical tumor manipulation as a major trigger. Panel C: Cardiovascular complications showing hypertensive crisis, catecholamine-induced cardiomyopathy (Takotsubo-like), arrhythmias, myocardial infarction from demand ischemia, and stroke from hypertensive crisis. Panel D: Metabolic and other features showing hyperglycemia (alpha-2 mediated insulin inhibition), weight loss despite adequate caloric intake, pallor from vasoconstriction, anxiety and panic attacks, and constipation from decreased GI motility. --- ### VIII. Pheochromocytoma - Diagnosis The diagnosis of pheochromocytoma requires biochemical confirmation before imaging studies. A systematic approach using appropriately sensitive tests minimizes false negatives while confirmatory testing addresses false positives. Biochemical testing represents the essential first step. Plasma free metanephrines (fractionated into metanephrine and normetanephrine) are the preferred first-line test, with sensitivity of 96-99%—making a negative result essentially rule out pheochromocytoma. Specificity is somewhat lower (85-89%), meaning some false positives occur. Twenty-four-hour urine fractionated metanephrines have slightly lower sensitivity (87-90%) but higher specificity (95-99%). Twenty-four-hour urine catecholamines have 85% sensitivity and 90% specificity. Chromogranin A can be measured but has variable sensitivity and lower specificity. Interpretation of biochemical results requires understanding thresholds. Elevations greater than 2-3 times the upper limit of normal are highly suggestive and warrant imaging and further workup. Borderline elevations (1-2 times upper limit) represent a diagnostic gray zone requiring confirmatory testing or repeat measurement under optimal conditions. Medications can cause false-positive results, making preparation important. Medications affecting catecholamine and metanephrine measurements can confound testing. Tricyclic antidepressants increase norepinephrine and normetanephrine through reuptake inhibition. MAO inhibitors increase catecholamines by blocking metabolism. Decongestants (phenylephrine, pseudoephedrine) can elevate norepinephrine. Acetaminophen may cause assay interference in some laboratories. Levodopa increases dopamine metabolites. Ideally, interfering medications should be discontinued 2 weeks before testing when clinically feasible. The clonidine suppression test helps differentiate true pheochromocytoma from false-positive results in borderline cases. Clonidine (0.3 mg orally) stimulates central α₂ receptors, suppressing sympathetic outflow. Plasma catecholamines are measured at baseline and 3 hours after clonidine. In normal individuals or patients with essential hypertension, norepinephrine decreases by 50% or more. In pheochromocytoma, catecholamine secretion is autonomous and fails to suppress. Imaging studies are performed only after biochemical confirmation to locate the tumor. CT of the adrenal glands detects more than 95% of adrenal pheochromocytomas, appearing as adrenal masses often with heterogeneous enhancement. MRI shows characteristic high signal intensity on T2-weighted images ("light bulb" sign) and is useful if CT is contraindicated. Functional imaging with MIBG (metaiodobenzylguanidine) scan uses a norepinephrine analog that is taken up by chromaffin tissue; it is useful for detecting metastatic disease and extra-adrenal tumors. PET scanning with ⁶⁸Ga-DOTATATE is particularly useful in SDHB mutation carriers; ¹⁸F-FDG PET is helpful for malignant disease. Panel A: Biochemical testing hierarchy showing plasma free metanephrines as preferred first-line test (96-99% sensitivity), 24-hour urine fractionated metanephrines as alternative (87-90% sensitivity), with interpretation thresholds of greater than 2-3 times upper limit for diagnosis and 1-2 times as borderline. Panel B: Medications causing interference including tricyclic antidepressants, MAO inhibitors, decongestants, and acetaminophen, with recommendation to discontinue interfering drugs 2 weeks before testing. Panel C: Clonidine suppression test protocol showing baseline catecholamines, 0.3 mg oral clonidine administration, 3-hour repeat measurement, with 50% or greater norepinephrine suppression expected in normal individuals and failure to suppress in pheochromocytoma. Panel D: Imaging sequence showing adrenal CT as first-line (detects over 95% of adrenal tumors), MRI with characteristic T2 bright signal, MIBG scan for functional and metastatic workup, and PET options (Ga-68-DOTATATE for SDHB carriers, FDG for malignant disease). --- ### IX. Pheochromocytoma - Management Management of pheochromocytoma centers on surgical resection after careful preoperative preparation with alpha-adrenergic blockade. Understanding the principles of perioperative management prevents catastrophic hypertensive crises and enables safe tumor removal. Preoperative preparation aims to block catecholamine effects and restore intravascular volume. Alpha-adrenergic blockade is initiated first, typically 10-14 days before surgery, to control hypertension and allow volume expansion. Blood pressure targets are less than 130/80 mmHg seated with systolic pressure greater than 90 mmHg when standing (to confirm adequate blockade without excessive orthostatic hypotension). Heart rate should be controlled to 60-70 bpm (beta-blockade added if needed). Liberal salt and fluid intake encourages volume expansion to counter the chronic volume contraction caused by catecholamine-induced vasoconstriction. Alpha-adrenergic blockade is the cornerstone of preoperative preparation. Phenoxybenzamine is the most commonly used agent; it is a non-selective, irreversible α-blocker with a long duration of action that provides consistent blockade. Starting dose is typically 10 mg twice daily, titrated upward based on blood pressure. Selective α₁-blockers (doxazosin, prazosin) are alternatives with shorter duration and potentially easier perioperative management. Side effects of alpha blockade include orthostatic hypotension, nasal congestion, and reflex tachycardia. The critical principle of "alpha before beta" must be understood. Beta-blockers should NEVER be started before adequate alpha-blockade is established. Beta-blockade alone would eliminate the vasodilatory effect of β₂ receptors, leaving α₁-mediated vasoconstriction unopposed. This can precipitate severe hypertensive crisis from unopposed alpha stimulation. Beta-blockers are added only after alpha-blockade to control reflex tachycardia. Beta-adrenergic blockade is added after adequate alpha-blockade for persistent tachycardia or arrhythmias. Non-selective beta-blockers (propranolol) or cardioselective agents (atenolol, metoprolol) may be used. Timing should be at least 2-3 days after alpha-blockade is established. Other medical therapies may be useful in specific situations. Metyrosine inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, thereby reducing catecholamine production. Calcium channel blockers (nicardipine, nifedipine) may be added for blood pressure control. Intraoperative magnesium sulfate can be used for arrhythmia control. Surgical treatment involves adrenalectomy after adequate preparation. Laparoscopic adrenalectomy is preferred for most adrenal tumors. Open surgery is reserved for large tumors, suspected malignancy, or technically difficult cases. Intraoperative management requires close hemodynamic monitoring with arterial line placement; intravenous phentolamine (alpha-blocker) or nitroprusside should be available for hypertensive crises during tumor manipulation. Following tumor removal, hypotension may occur as the catecholamine source is removed; volume support and vasopressors should be available. Malignant pheochromocytoma is defined by the presence of metastases to non-chromaffin tissue (bone, liver, lung, lymph nodes). Metastatic disease occurs in approximately 10-15% of adrenal tumors but is higher in extra-adrenal paragangliomas and SDHB mutation carriers (30-40%). Treatment options include surgical resection of primary and metastatic disease when feasible, ¹³¹I-MIBG therapy for MIBG-avid tumors, systemic chemotherapy (CVD regimen: cyclophosphamide, vincristine, dacarbazine), and targeted therapies (sunitinib, temozolomide). Panel A: Preoperative preparation timeline showing alpha-blockade initiation 10-14 days before surgery with phenoxybenzamine starting at 10 mg twice daily, titrated upward to blood pressure target less than 130/80 seated and systolic greater than 90 standing. Panel B: Alpha before beta principle with warning illustration showing that beta-blockade alone eliminates beta-2 vasodilation leaving alpha-1 vasoconstriction unopposed, risking severe hypertensive crisis, with beta-blockers added only after adequate alpha-blockade. Panel C: Surgical approach showing laparoscopic adrenalectomy as preferred technique with intraoperative arterial line monitoring, IV phentolamine and nitroprusside available for hypertensive crises during tumor manipulation, and volume support for post-removal hypotension. Panel D: Malignant disease treatment options including surgical resection of primary and metastatic disease, I-131-MIBG therapy for MIBG-avid tumors, CVD chemotherapy regimen, and targeted therapies (sunitinib, temozolomide) with 10-15% overall malignancy rate. --- ### X. Hereditary Pheochromocytoma Syndromes The recognition that 30-40% of pheochromocytomas and paragangliomas are hereditary has transformed clinical practice. Genetic testing is now recommended for all patients, enabling identification of at-risk family members and informing surveillance and treatment decisions. The overview of hereditary disease reflects current understanding. Unlike the historical "10% familial" estimate, current evidence recognizes hereditary disease in 30-40% of patients with pheochromocytoma or paraganglioma. Multiple genes are implicated, each with distinct clinical features and risks. Genetic testing should be offered to all patients with pheochromocytoma or paraganglioma. Identification of a pathogenic variant enables cascade genetic testing and surveillance of at-risk family members, potentially preventing morbidity and mortality from undiagnosed tumors. Multiple endocrine neoplasia type 2 (MEN2) results from activating mutations in the RET proto-oncogene. MEN2A includes pheochromocytoma (approximately 50% penetrance), medullary thyroid carcinoma (MTC, 95% penetrance), and primary hyperparathyroidism (20-30%). MEN2B includes pheochromocytoma (approximately 50%), MTC (100%, earliest and most aggressive), marfanoid body habitus, and mucosal neuromas (lips, tongue, eyelids). Pheochromocytomas in MEN2 are typically adrenal, frequently bilateral (50-80%), and almost always benign. They predominantly secrete epinephrine. RET genetic testing guides timing of prophylactic thyroidectomy in MTC. Von Hippel-Lindau (VHL) syndrome results from mutations in the VHL tumor suppressor gene. Manifestations include pheochromocytoma (approximately 20% penetrance), hemangioblastomas of the CNS and retina, clear cell renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and endolymphatic sac tumors. Pheochromocytomas in VHL are frequently bilateral, often secrete primarily norepinephrine (due to lower PNMT expression), and are generally benign. Surveillance for pheochromocytoma in VHL patients should begin in early childhood (annual biochemical testing from age 5). Neurofibromatosis type 1 (NF1) results from mutations in the NF1 gene encoding neurofibromin. The classic features include neurofibromas, café-au-lait spots, Lisch nodules, and optic pathway gliomas. Pheochromocytoma occurs in approximately 3-5% of NF1 patients. Tumors are typically adrenal, unilateral, and benign. SDH (succinate dehydrogenase) mutations represent an important cause of hereditary paraganglioma and pheochromocytoma. SDH is a mitochondrial enzyme in the Krebs cycle, and mutations in genes encoding its subunits (SDHA, SDHB, SDHC, SDHD, SDHAF2) cause hereditary paraganglioma syndromes. SDHB mutations carry the highest malignancy risk (30-40% metastatic) and are associated with extra-adrenal and abdominal tumors. SDHD mutations are associated with head and neck paragangliomas; inheritance is paternal (tumors develop only when the mutation is inherited from the father). SDHC and SDHA mutations have lower penetrance. Genetic testing recommendations reflect the high prevalence of hereditary disease. All patients with pheochromocytoma or paraganglioma should be offered genetic testing. Testing is particularly high-yield in patients with bilateral tumors, extra-adrenal location, young age at diagnosis, family history, or malignant disease. Multi-gene panels testing all known susceptibility genes are typically used. First-degree relatives of mutation carriers should undergo cascade genetic testing, and those who test positive require lifelong surveillance. Panel A: Major hereditary syndromes comparison table showing MEN2 (RET gene, MTC, pheochromocytoma, hyperparathyroidism), VHL (VHL gene, hemangioblastomas, renal cell carcinoma, pheochromocytoma), NF1 (NF1 gene, neurofibromas, cafe-au-lait spots), with gene, tumor spectrum, and pheochromocytoma characteristics for each. Panel B: SDH mutation details showing SDHB with 30-40% metastatic risk (highest malignancy), SDHD associated with head and neck paragangliomas with paternal inheritance, and SDHC and SDHA with lower penetrance, all affecting mitochondrial Krebs cycle function. Panel C: Genetic testing recommendations showing all patients with pheochromocytoma or paraganglioma should be offered multi-gene panel testing, with particularly high yield in bilateral tumors, extra-adrenal location, young age, family history, or malignant disease. Panel D: Surveillance protocols for mutation carriers showing annual biochemical testing (plasma metanephrines), VHL screening from age 5, MEN2 screening for pheochromocytoma and MTC, and cascade genetic testing for first-degree relatives of identified carriers. --- ## Summary The adrenal medulla derives from neural crest and functions as a modified sympathetic ganglion, with chromaffin cells releasing catecholamines into the circulation rather than at synaptic junctions. The portal blood supply from the cortex provides high cortisol concentrations that induce PNMT, explaining why the adrenal medulla is the primary source of epinephrine. Catecholamine synthesis proceeds from tyrosine through L-DOPA, dopamine, and norepinephrine to epinephrine, with tyrosine hydroxylase as the rate-limiting enzyme. Secretion occurs by exocytosis in response to preganglionic acetylcholine, and metabolism by COMT and MAO generates the metanephrines used for diagnostic testing. Pheochromocytoma presents with hypertension and the classic triad of headache, diaphoresis, and palpitations. Diagnosis requires biochemical confirmation, with plasma free metanephrines being the most sensitive test, followed by imaging localization. Treatment requires alpha-adrenergic blockade first (never beta-blockers alone, due to risk of unopposed alpha stimulation), followed by beta-blockade if needed, then surgical resection. Laparoscopic adrenalectomy is preferred with careful intraoperative hemodynamic management. Hereditary disease occurs in 30-40% of cases, far higher than previously recognized. Genetic testing should be offered to all patients, and affected families require cascade testing and lifelong surveillance. --- ## Key Terms | Term | Definition | |------|------------| | Chromaffin cells | Catecholamine-producing cells of the adrenal medulla and extra-adrenal paraganglia | | PNMT | Phenylethanolamine N-methyltransferase; enzyme converting norepinephrine to epinephrine, induced by cortisol | | Pheochromocytoma | Catecholamine-secreting tumor arising from adrenal medullary chromaffin cells | | Paraganglioma | Extra-adrenal catecholamine-secreting tumor arising from paraganglia | | Metanephrines | Catecholamine metabolites (metanephrine and normetanephrine) used for pheochromocytoma diagnosis | | Alpha blockade | First-line preoperative preparation for pheochromocytoma, blocking α-adrenergic vasoconstriction | | SDHx mutations | Succinate dehydrogenase gene mutations causing hereditary paraganglioma syndrome | | Chromogranin A | Secretory granule protein released with catecholamines; tumor marker for pheochromocytoma | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*