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]

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, Insulinoma, Renovascular hypertension, Hypoglycemia and drugs.

DIFFERENTIAL DIAGNOSIS — In addition to pseudopheochromocytoma , the following diagnoses should be strongly considered among patients presenting with paroxysmal hypertension:

Pseudopheochromocytoma most likely involves activation of the sympathetic system; this has been inferred from the following observations [5-11]:

●Paroxysmal nature

●Association with tachycardia in some patients

●Increase in plasma catecholamines documented during attacks [5]

●Increase in baseline plasma epinephrine and metanephrines [9]

●Response to alpha/beta blockade [8]

The mechanism that underlies sympathetic activation is unclear but appears to involve emotional factors.

CLINICAL MANIFESTATIONS — In patients in whom the diagnosis of a pheochromocytoma has been excluded, who are considered to have pseudopheochromocytoma, hypertensive episodes are generally characterized by the following three features:

●An abrupt elevation of blood pressure (which can be greater than 200/110 mmHg in some patients) that is documented by a clinician or home blood pressure monitor

●Equally abrupt onset of distressful physical symptoms, such as headache, chest pain, dizziness, nausea, palpitations, flushing, and diaphoresis

●Attacks are not triggered by fear or panic, although fear does occur as a consequence of the frightening physical symptoms

The duration of episodes can range from 10 minutes to many hours, with frequency ranging from several per day to once every few months. Between episodes of paroxysmal hypertension, the blood pressure can be elevated (due to inadequately treated chronic hypertension), normal, or low (due to antihypertensive therapy initiated during an episode of paroxysmal hypertension).

Psychological characteristics — Patients with pseudopheochromocytoma usually insist that episodes are unrelated to emotional distress. This feature has tended to discourage consideration of a causal role for emotional factors. However, details of patients' psychosocial history and the success of psychologically based intervention in some cases (as described below) suggest that the disorder is usually related to emotions that have been kept from conscious awareness and therefore are not reported.

In the largest study to date, 14 of 21 patients (67 percent) acknowledged a past history of severe emotional trauma (such as the Holocaust or severe childhood trauma) or prolonged physical or emotional abuse [8]. They uniformly insisted that those events bore no lingering emotional impact. The remaining seven individuals did not report a history of overt emotional trauma or abuse, but careful interviewing indicated a pattern of minimizing awareness of distressful emotions and of not confiding in anyone.

Individuals with this disorder may feel some degree of emotional distress but seem immune to the more severe emotional distress experienced at times by most other people.

●Labile hypertension White coat hypertension, more commonly known as white coat syndrome, is a phenomenon in which patients exhibit elevated blood pressure in a clinical setting but not in other settings.^[1] The prevalence of white coat hypertension is approximately 13%.^[2] Risk factors for white coat hypertension in observational studies include age, female sex, and being a non-smoker. The higher the blood pressure in the clinical setting, the lower the probability of white coat hypertension.^[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. Ambulatory monitoring has been found to be a more practical and reliable method in detecting patients with white coat hypertension and for the prediction of target organ damage. The 2013 ESC/ESH recommendations recommend that white coat hypertension be confirmed within 3-6 months of initial diagnosis and that close follow-up and periodic out-of-office BP measurements be obtained.^[1] The treatment of white coat hypertension remains controversial.^[3] Finally, the risk of target organ damage and prognosis among patients with white coat hypertension is still unknown. Although white coat hypertension was initially considered intermediate in risk between normal blood pressure and hypertension, larger subsequent meta-analyses have not demonstrated a significant difference in outcomes between patients with white coat hypertension and those with normal blood pressure levels.^[2][4][5]

●Panic disorder Panic disorder can replicate many of the symptoms of pheochromocytoma because it is associated with increased sympathetic activity. Hypertension in these patients occurs primarily during treatment with a tricyclic antidepressant drug, which may increase the degree of sympathetic arousal.

Pheochromocytoma — The diagnosis of pheochromocytoma must be excluded in all patients with unprovoked paroxysmal hypertension. Assays of plasma or urine catecholamines are diagnostic in 95 percent of patients with symptoms, and the high sensitivity of the plasma metanephrine assay is also documented

pseudopheochromocytoma insist that the disorder is unrelated to psychologic factors.

Panic disorder — Panic disorder is characterized by episodes of fear or panic, and is commonly associated with physical symptoms such as chest pain, headache, palpitations, flushing, and dizziness, along with some degree of blood pressure elevation [16-20]. Panic disorder and pseudopheochromocytoma share similar physical symptoms, and both respond to treatment with an antidepressant agent. As mentioned above, panic disorder is present in as many as 40 percent of patients evaluated for pseudopheochromocytoma,

However, the two disorders differ from each other in that the presentation of pseudopheochromocytoma is dominated by autonomic manifestations (ie, paroxysmal hypertension). In patients with pseudopheochromocytoma, fear occurs only in response to the physical symptoms. By contrast, panic disorder is dominated by emotional manifestations (ie, panic), and accompanying blood pressure changes are milder.

The most critical clinical difference is that, in the absence of antecedent panic or emotional distress, pseudopheochromocytoma is viewed as an unexplained medical disorder. Therefore, clinicians and patients rarely consider an emotion-based cause or treatment because, by definition, patients fail to report any triggering emotional distress.

Other causes of paroxysmal hypertension — Many additional disorders may present with paroxysmal hypertension, including the following:

●Hyperthyroidism.: symptoms of hyperthyroidism include weight loss, heat intolerance, tremor, palpitations, anxiety, increased bowel disturbances , and shortness of breath. Goiter, skin flushing and eye proptosis are common clinical findings.

Increased sensitivity of beta receptors in heart to catecholamines due to effect of thyroid hormones increase cardiac work and output and systolic hypertension. low thyroid-stimulating hormone (TSH) high free thyroxine (T4) and triiodothyronine (T3) concentrations.In patients with subclinical hyperthyroidism, TSH is below normal (but usually >0.05 mU/L)and serum free T4, T3, and free T3 are normal.

●migraine headaches (1) the prodrome, which occurs hours or days before the headache, (2) the aura, which immediately precedes the headache, (3) the pain phase, also known as headache phase and (4) the postdrome phase.

• Conjunctival injection may be present

• Horner's syndrome ^[1] may be present
• Adie type pupil ^[2] may be present

• Cranial/ cervical muscle tenderness may be present
• Listen for bruit at neck and head for clinical sights of arteriovenous malformation.

CT is indicated in patients with: ^[1] [2]

• Abnormal physical examination
  • Increase of headache's frequency
  • Poor coordination
  • Focal neurologic signs
  • Headache's awakening the patient at night^[3][4]
• Atypical aura: sudden onset, lasting more than 1 hour, always at the same side and/or without visual symptoms
• Migraine attacks that begin after 50 years of age

CT is not indicated in:

• Patients with a diagnosis of migraine in accordance with the criteria for migraine.
• Differentiating a migraine from other primary headaches

●Renovascular hypertension

• Age of hypertension < 30 years and > 55 years
• Abrupt onset of hypertension
• Accelerated hypertension that was previously well-controlled
• Refractory hypertension to 3 anti-hypertensive medications
• Malignant hypertension

(bruit) can be heard over the abdomen.

Diagnosis by Duplex ultrasonography is considered class I recommendation. It 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 intestinal gas.^[1]

●Central nervous system lesions, such as stroke, tumor, hemorrhage, compression of lateral medulla, and trauma

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.

Baroreflex failure, which is characterized by marked and frequent fluctuations in blood pressure, with both high and low readings . It is caused by hypofunctioning of the 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.

●Seizure disorder.

Symptoms experienced by a person during a seizure depend on where in the brain the disturbance in electrical activity occurs. Recent studies show that seizures happen in sleep more often than was thought. A person having a tonic-clonic seizure may cry out, lose consciousness and fall to the ground, and convulse, often violently. A person having a complex partial seizure may appear confused or dazed and will not be able to respond to questions or direction. Some people have seizures that are not noticeable to others. Sometimes, the only clue that a person is having an absence seizure is rapid blinking or a few seconds of staring into space.

• Change in alertness; the person cannot remember a period of time
• Mood changes, such as unexplainable fear, panic, joy, or laughter
• Change in sensation of the skin, usually spreading over the arm, leg, or trunk
• Vision changes, including seeing flashing lights
• Rarely, hallucinations (seeing things that aren't there)
• Falling, loss of muscle control, occurs very suddenly
• Muscle twitching that may spread up or down an arm or leg
• Muscle tension or tightening that causes twisting of the body, head, arms, or legs
• Shaking of the entire body
• Tasting a bitter or metallic flavor

Many seizures, especially in children, are preceded by tachycardia that frequently persists throughout the seizure. This early increase in heart rate may supplement an aura as a physiological warning sign of an imminent seizure.

An isolated abnormal electrical activity recorded by an electroencephalography examination without a clinical presentation is called subclinical seizure. They may identify background epileptogenic activity, as well as help identify particular causes of seizures.

●Carcinoid syndrome: hypertensive crisis occurs with malignant carcinoid syndrome should be distinguished from pheochromocytoma. Patient

CLINICAL FEATURES Cutaneous flushing Venous telangiectasia Diarrhea Bronchospasm Cardiac valvular lesions : tricusped incompitence.

• Urinary excretion of 5-HIAA
• Urinary excretion of serotonin
• Chromogranin concentration Chromogranins (designated as A, B, and C) are proteins that are stored and released with peptides and amines in a variety of neuroendocrine tissues
• Blood serotonin concentration
• Plasma 5-HIAA concentration

CT is recommended for evaluation of all patients with carcinoid tumors

●Drugs – cocaine, lysergic acid diethylamide, amphetamine, and clozapine . Sympathomimetic drugs that can induce symptoms simulating pheochromocytoma include high-dose phenylpropanolamine (a popular over-the-counter decongestant and appetite suppressant), cocaine, amphetamines, phencyclidine, epinephrine, phenylephrine, and terbutaline, and the combination of a monoamine oxidase (MAO) inhibitor and ingestion of tyramine-containing foods [7,26-29]. Mercury intoxication also can mimic pheochromocytoma, producing both hypertension and elevated urine and plasma catecholamines [30].

●Baroreflex failure, which is characterized by marked and frequent fluctuations in blood pressure, with both high and low readings [23]. It is caused by hypofunctioning of the 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.

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