Pheochromocytoma differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D[3]

Overview

Pheochromocytoma must be differentiated from other causes of paroxysmal hypertension including severe paroxysmal hypertension (pseudopheochromocytoma), panic disorder, factitious hypertension, carcinoid syndrome, migraine headache, hyperthyroidism, renovascular hypertension, hypoglycemia, labile hypertension (White coat hypertension), stroke, compression of the lateral medulla, seizures, baroreflex failure and drugs.

Differentiating pheochromocytoma from other diseases

Pheochromocytoma must be differentiated from other causes of paroxysmal hypertension. The differentials include:

Disease	Symptoms	Signs	Investigations
Pheochromocytoma	The symptoms of a pheochromocytoma are those of sympathetic nervous systemhyperactivity and include: Palpitations (especially in epinephrine producing tumors)[3] Anxiety  Sweating Headaches (90 % of patients) Paroxysmal attacks of hypertension May be asymptomatic (incidentally discovered in MEN syndrome patients)	Tachycardia Hypertension, including paroxysmal (sporadic, episodic) high blood pressure, which sometimes can be more difficult to detect. Orthostatic hypotension	High-risk patients: Plasma fractionated metanephrines 24-hour urinary fractionated metanephrines, catecholamines Imaging studies (CT scan, MRI and  iodine-123-meta-iodobenzylguanidine or MIBG scintiscan)[2] Low-risk patients: 24-hour urinary fractionated catecholamines and metanephrines[4]
Pseudopheochromocytoma	Paroxysmal activation of the sympathetic system causing: Emotional distress Acute onset of high blood pressure Headache Chest pain Nausea Palpitations Flushing Duration of attacks ranges from minutes to hours Physical symptoms occur before feeling fear	Hypertension Tachycardia	Increase in plasma catecholamines between and during attacks.
Panic attacks	Paroxysms of increased sympathetic activity Episodes of fear or panic attacks Chest pain Headache Palpitations Flushing Response to antidepressants Fear precedes physical symptoms.		Laboratory studies that can exclude medical disorders other than panic disorder include: Serum electrolytes Serum glucose Cardiac enzymes Urine toxicology screening
Labile hypertension (White coat hypertension)	Elevated blood pressure in a clinical setting but not in other settings[1]		Ambulatory blood pressure monitoring and patient self-measurement using a home blood pressure monitoring device are being increasingly used to differentiate patients with white coat hypertension from patients with true hypertension.
Hyperthyroidism	Weight loss Heat intolerance Tremors Palpitations Anxiety Increased bowel disturbances Shortness of breath	Goiter Skin flushing Proptosis Increased sensitivity of beta receptors in the heart to catecholamines due to an effect of thyroid hormones increase cardiac work and output Systolic hypertension	Low thyroid-stimulating hormone (TSH) High free thyroxine (T4) concentration High triiodothyronine (T3) concentration
Renovascular hypertension	Common in individuals < 30 years or > 55 years Abrupt onset of hypertension Accelerated hypertension that was previously well-controlled Refractory hypertension to 3 anti-hypertensive medications Headache Nausea Subconjunctival hemorrhage	Bruit can be heard over the abdomen	Duplex ultrasonography may be used as an initial screening tool for diagnosis of atherosclerotic renal artery stenosis Ultrasonography (might not be very accurate in obese patients or those with intestinal gas)[1]
Stroke and compression of lateral medulla (Lateral medullary syndrome)	Extensive unilateral infarction of the brain stem in the region of the nucleus tractus solitarius may result in partial baroreflex dysfunction, increased sympathetic activity, and neurogenic paroxysmal hypertension		CT shows mass compressing lateral medulla or infarction in the same area
Seizures	According to type; it may be focal or generalized, clinical or subclinical: tonic-clonic seizure: Repetitive twitches of arm and legs Tongue bitting Loss of consciousness Symptoms occur suddenly and may persist Muscle tension or tightening that causes twisting of the body, head, arms, or legs Amnesia Mood changes (fear, panic, or laughter) Change in sensation of the skin over the arm, leg, or trunk Vision changes and light flashes Hallucinations Tasting a bitter or metallic flavor Complex partial seizure: Confused or dazed and Not be able to respond to questions or direction Absence seizure: Rapid blinking Few seconds of staring into space		Abnormal electroencephalography Positive test without a clinical presentation is called a sub-clinical seizure
Carcinoid syndrome	Hypertensive crisis occurs with malignant carcinoid syndrome. Symptoms include: Severe chest pain Severe headache Confusion and blurred vision Nausea and vomiting Severe anxiety Shortness of breath Seizures Unresponsiveness	Cutaneous flushing Venous telangiectasia Diarrhea Bronchospasm Cardiac valvular lesions (tricuspid incompetence)	High urinary excretion of 5-HIAA High urinary excretion of serotonin High chromogranin concentration(Chromogranin(A, B, and C) are proteins that are stored and released with peptides and amines in a variety of neuroendocrine tissues) CT is recommended for evaluation of all patients with carcinoid tumors.
Migraine headaches	Prodrome: Occurs hours or days before a headache Aura Immediately precedes the headache Pain phase Also known as headache phase Postdrome phase	Conjunctival injection Horner's syndrome[1]  Adie's pupil [2]  Cranial/ cervical muscle tenderness  Bruit at neck and head for clinical signs of an arteriovenous malformation Photosensitivity	CT is indicated in patients with:[1][2] Abnormal physical examination: Increase of headache's frequency Poor coordination Focal neurologic signs Headaches awakening the patient at nigt[3][4] Atypical aura Sudden onset Lasting more than 1 hour Always on the same side With or without visual symptoms Migraine attacks that begin after 50 years of age CT is not indicated in: Patients with a diagnosis of a migraine in accordance with the criteria for migraine Differentiating a migraine from other primary headaches
Drugs	Sympathomimetic drugs that can induce symptoms simulating pheochromocytoma include: High-dose phenylpropanolamine Cocaine Amphetamines Lysergic acid diethylamide (LSD) Phenylcyclidine (PCP) Combination of a monoamine oxidase (MAO) inhibitor and ingestion of tyramine-containing foods.	Disturbed consciousness Nasal septum perforation in cocaine addiction Needle marks on the skin History of antidepressantintake	Urine toxicology screening
Baroreflex failure	Marked and frequent fluctuations in blood pressure, with both high and low readings It is caused by hypofunctioning of baroreflexes that normally buffer blood pressure fluctuations The disorder is usually a result of injury to carotid baroreceptors, with most patients reporting a history of neck irradiation or surgery		Neck CT scan

Disease	Prominent clinical features	Investigations
Hyperthyroidism	The main symptoms include: Palpitations Insomnia Anxiety Weight loss Heat intolerance Diarrhea Depending on the underlying diagnosis, the patient might have exophthalmus or goiter	The patient usually has elevated T3 and T4 TSH might be increased or decreased depending on the underlying cause Thyroid stimulating antibodies (TSI) might be increased in cases of Graves’ disease
Essential hypertension	Most patients with hypertension are asymptomatic at the time of diagnosis. Common symptoms are listed below: Headache Blurry vision Dyspnea Epistaxis Tinnitus Fatigue Drowsiness	JNC 7 recommends the following routine laboratory tests before initiation of therapy for hypertension: 12-Lead electrocardiogram (ECG) Urinalysis, including urinary albumin excretion or albumin/creatinine ratio Blood glucose Blood hematocrit Serum electrolytes, especially potassium Serum calcium Lipid profile: Total cholesterol, LDL, HDL, triglycerides Creatinine or estimated GFR
Generalized anxiety disorder	According to DSM V, the following criteria should be present to fit the diagnosis of generalized anxiety disorder: The presence of sense of apprehension or fear toward certain activities for most of the days for at least 6 months Difficulty to control the apprehension Associated restless, fatigue, irritability, difficult concentration, muscle tension or sleep disturbance (only one of these manifestations) The anxiety or the physical manifestations must affect the social and the daily life of the patient Exclusion of another medical condition or the effect of another administered substance Exclusion of another mental disorder causing the symptoms	-
Menopause	The perimenopausal symptoms are caused by an overall drop, as well as dramatic but erratic fluctuations, in the levels of estrogens, progestin, and testosterone. Some of these symptoms such as formication etc may be associated with the hormone withdrawal process. Vasomotor instability in the form of hot flushes, including night sweats and sleep disturbances Urogenital atrophy causing itching, dryness, bleeding, watery discharge, urinary frequency, urinary urgency and urinary incontinence Skeletal symptoms in the form of osteoporosis (gradually developing over time), artharlgia, myalgia and back pain Psychological manifestations such as mood disturbance, irritability, fatigue, memory loss and depression Sexual disorders: decreased libido, vaginal dryness, problems reaching orgasm and dyspareunia	B-HCG should always be done first to rule out pregnancy especially in women under the age of 45 years FSH can be measured but it can be falsely normal or low TSH, T3 and T4 to rule out thyroid abnormalities Prolactin can be measured to rule out prolactinoma as a cause of menopause
Opioid withdrawal disorder	According to DSM V, the following criteria should be present to fit the diagnosis of opioid withdrawal: Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e.,several weeks or longer) or administration of an opioid antagonist after a period of opioid use. Development of three or more of the following criteria minutes to days after cessation of drug use: dysphoric mood, nausea or vomiting, muscle aches, Lacrimation or rhinorrhea, pupillary dilation, piloerection, or sweating, diarrhea, yawning, fever, and insomnia. The signs or symptoms mentioned above must cause impairment of the daily functioning of the patient. The signs or symptoms mentioned above must not be attributed to other medical or mental disorders.	Urine drug screen to rule out any other associated drug abuse Routine blood work such as electrolytes and hemoglobin to rule out any associated disease explaining the symptoms
Pheochromocytoma	The hallmark symptoms of a pheochromocytoma are those of sympathetic nervous system hyperactivity, symptoms usually subside in less than one hour and they may include: Palpitations especially in epinephrine producing tumors. Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension but some patients have normal blood pressure. It may be asymptomatic and discovered by incidence screening especially MEN patients. Please note that not all patients with pheochromocytoma experience all classical symptoms.	Diagnostic lab findings associated with pheochromocytoma include: Elevated plasma and urinary catecholamines and metanephrines Elevated urinary vanillyl mandelic acid