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Paroxysmal hypertension in a 48-year-old woman Jennifer Hunt1 and Julie Lin1

1Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

emergency department and found her blood pressure to be CASE PRESENTATION 260/140 mm Hg. She had seen a medical professional at least A 48-year-old woman was referred for a second opinion a dozen times during those 18 months and was hospitalized regarding paroxysmal hypertension. At the time of at least three times for a period of 3 to 4 days while referral, she had an 18-month history of acute undergoing examination for secondary causes of hyperten- hypertensive crisis necessitating hospitalization. She had sion. In recent months, she had noted an acceleration in the already undergone evaluation by primary care and frequency of the episodes from once or twice per month to endocrinology prior to this presentation. three to four times per week. The patient reported that she Prior to 18 months ago, she had no history of often left the emergency room with improved but still hypertension and her past medical history was only elevated blood pressure in the 160/90 range. Her physicians significant for two previous pregnancies, neither of which tried multiple single-agent medications, including amlodi- was accompanied by hypertension. She described herself pine 5 mg daily, HCTZ 25 mg daily, metoprolol 100 mg daily, as healthy and exercised daily prior to onset of these and labetolol 200 mg twice daily, which were variably titrated hypertensive attacks. She generally felt well rested. upwards during hypertensive episodes. Between attacks, her She saw her primary care physician regularly for health blood pressure was 100–120mm Hg systolic or lower; care maintenance and reported that her blood pressure however, she experienced symptomatic hypotension between prior to 18 months ago usually ranged from 110 to the episodes necessitating that the medications be reduced or 120 mm Hg systolic, with a heart rate of 60–70 beats stopped entirely. per minute. She had no family history of hypertension. The results of multiple plasma and 24-h urine tests, She was divorced and had two children. She did including plasma renin and aldosterone, urine catechola- not smoke, drank one to two cups of coffee per day, mines, and 5-hydroxyindoleacetic acid (5-HIAA) (at least drank three to four glasses of wine in the evenings, one of which was collected during a hypertensive episode) denied illicit drug use, and had no known drug allergies. were reviewed by us and were normal and not suggestive of At the time of our initial evaluation, she was taking pheochromocytoma, primary aldosteronism, or carcinoid atenolol 25 mg daily as prescribed by her primary syndrome (Table 1). A fundoscopic examination documented care physician. She denied use of non-steroidal from at least one of her emergency room visits was stated as anti-inflammatory drugs, vitamins, herbals, or other normal. She had also undergone an abdominal computed over the counter medications. tomographic scan that demonstrated no adrenal masses and normal appearing kidneys. An echocardiogram performed a few months prior to our evaluation, however, did have evidence of concentric left ventricular hypertrophy. Beginning 18 months ago, she described her hypertensive On examination, she was a healthy-appearing woman in episodes as sudden, unprovoked, unrelated to stress or panic, no distress. Her blood pressure was 153/99 mm Hg with a and accompanied by various symptoms including headache, pulse of 63, she weighed 138 pounds (62.6 kg) with a height nausea, tremors, and diarrhea. She described an accompany- of 65.5 inches (166 cm), and her body mass index was À2 ing sense of dread or panic though only after the other 22.5 kg m . Her physical examination was unremarkable. symptoms manifested. She was not aware that these episodes She did not have enlarged tonsils or any craniofacial or soft included hypertension until she sought care in a local tissue abnormalities. No thyroid abnormalities, skin changes, or abdominal bruits were detected. Fundoscopic examination Correspondence: Julie Lin, Renal Division, Department of Medicine, was unremarkable. A urinalysis was normal and urine Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, microscopy was negative. Electrolytes were unremarkable Boston, Massachusetts 02115, USA. E-mail: [email protected] showing creatinine at 0.7 mg per 100 ml and serum Kidney International (2008) 74, 532–535; doi:10.1038/KI.2008.6; potassium at 3.9 mg per 100 ml. published online 27 February 2008 On further questioning with regard to psychological Received 10 April 2007; revised 7 November 2007; accepted 13 stressors, she said that has been divorced for 5 years and November 2007; published online 27 February 2008 had a history of physical and emotional abuse by her

532 Kidney International (2008) 74, 532–535 J Hunt and J Lin: Paroxysmal hypertension in a 48-year-old woman the renal consult

ex-husband. She reported that she had been in psychotherapy CLINICAL FOLLOW-UP for several years with a non-physician psychotherapist and We continued atenolol, added doxazosin 1 mg twice per day, was not on any psychiatric medications. She is a single and added paroxetine 10 mg per day to her medical regimen. mother of two school-aged children and currently attempting She came for follow-up 3 weeks later and reported no new to start a new business. She felt stress with regard to her hypertensive crisis since starting the new regimen. Her usual business, as it would be her primary means of income. systolic blood pressure was around 110 mm Hg. She still She was open about her alcohol intake, but denied signs experienced systolic blood pressures in the range of 150 to or symptoms consistent with dependence. Her alcohol intake 160 mm Hg, but only when exercising, an activity that she of 3–4 glasses of wine per day has been unchanged for 10 recently resumed. A telephonic interview 4 months later years and was confirmed by previous primary care notes in revealed no further hypertensive episodes and a maximum the medical record. When questioned about her specific systolic blood pressure of 130 mm Hg, even while exercising. activities and frame of mind on the day or two preceding She continued to drink 3–4 glasses of wine per day, and a number of her recent attacks, she adamantly denied overt the psychosocial stressors of starting a business and anxiety, fear, or emotional distress. In fact, one of the most difficult interactions with her ex-husband were unchanged recent attacks occurred on a weekend while she was at at follow-up. the beach relaxing with her oldest daughter and enjoying a pleasant afternoon. DISCUSSION In the clinical evaluation of the patient with a recent onset of CLINICAL DIAGNOSIS paroxysmal hypertension, secondary causes of hypertension She was clinically diagnosed with pseudopheochromocytoma. must be investigated. The most common causes of secondary hypertension, whether sustained or episodic, include reno- vascular disease, primary aldosteronism, renal parenchymal disease, obstructive sleep apnea, hyperthyroidism, Cushing’s Table 1 | Laboratory results syndrome, and pheochromocytoma.1 The syndrome of a Electrolytes Urinalysis and urine microscopy catecholamine-secreting pheochromocytoma (Table 2) is one Na: 134 mmol lÀ1 Specific gravity, 1.004 of the most recognized form of secondary hypertension, À1 (ref. 136–142mmol l ) although among the rarest form ultimately diagnosed with K: 3.9 mmol lÀ1 (ref. 3.5–5.0mmol lÀ1) pH 6.5 Cl: 98 mmol lÀ1 (ref. 98–108mmol lÀ1) No albumin, ketones, or nitrites only 0.1–0.6% of hypertension cases attributed to this À1 2 CO2: 27 mmol l RBC/hpf: 3–5 etiology. Pheochromocytoma must be considered, however, (ref. 23–32mmol lÀ1) as it is potentially lethal when unrecognized as it can lead to BUN: 8 mg per 100 ml (ref. 9–25mg WBC/hpf: none cerebral vascular accidents or myocardial infarctions as a per 100 ml) 3 Creatinine: 0.7 mg per 100 ml Casts: none consequences of the effects of secreted catecholamines. (ref. 0.7–1.3mg per 100 ml) The term pseudopheochromocytoma has been used to describe paroxysmal hypertension with a spectrum of signs Other plasma tests 24-h urine collection and symptoms consistent with catecholamine excess, but in Plasma renin: 1.5 ng mlÀ1 Total volume, 2650 ml (ref. 0.2–1.6ng mlÀ1) the absence of a clinical diagnosis of pheochromocytoma. It 4 Plasma aldosterone: 27.9 ng per Na: 130 mmol was used by Kuchel in 1981 to describe a hyperadrenergic 100 ml (ref. 4–31ng per 100 ml) (ref. 75–200mmol) form of essential hypertension with labile blood pressure, low À1 TSH 1.6 mIU l (normal 0.5–5.0) K: 53 mmol (ref. 40–80mmol) conjugated catecholamines, and commonly associated with Creatinine: 1193 mg (ref. 800–1800mg) emotional triggers. He reinforced the predominance of overt emotionally provoked bouts of hypertension in this popula- Other urine tests Aldosterone: 13.8 mcg tion in a 10-year retrospective analysis from 1998.5 Similarly Urine toxicology screen: negative (ref. 6–25mcg) 6 Epinephrine: 8 mcg in 1985, Takabatake et al. described a series of patients (ref. 0–25mcg) meeting these criteria. Norepinephrine: 61 mcg The term pseudopheochromocytoma has since been (ref. 0–100mcg) variably used in the literature to describe syndromes of Dopamine: 231 mcg (ref. 60–440mcg) Free cortisol: 2.7 mcg Table 2 | Common symptoms associated with (ref. 0–45mcg) pheochromocytoma Normetanephrines: 419 mcg (ref. 50–650mcg) Sustained or episodic hypertension Metanephrines: 117 mcg Headache (ref. 30–350mcg) Diaphoresis Vanillyl mandelic acid (VMA): Palpitations 2.1 mg (0–7mg) Pallor 5-HIAA: 4 mg (ref. 0–8mg) Nausea Flushing BUN, blood urea nitrogen; 5-HIAA, 5-hydroxyindoleacetic acid; hpf, high-power field; TSH, thyroid-stimulating hormone. Psychological symptoms

Kidney International (2008) 74, 532–535 533 the renal consult J Hunt and J Lin: Paroxysmal hypertension in a 48-year-old woman

paroxysmal hypertension that may include biochemical states or panic attacks, although she did become emotionally evidence of catecholamine excess in the absence of an distressed when a hypertensive crisis was underway. Thyro- identifiable tumor. Anti-Parkinsonian drugs and obstructive toxicosis and carcinoid were ruled out by laboratory analysis, sleep apnea have been described to cause elevations in plasma and there was no history or evidence of alcohol withdrawal. catecholamines resulting in labile hypertension.7,8 Pre- Pseudopheochromocytoma (as defined above) was therefore eclampsia resulting in an elevation of urinary catecholamine diagnosed and treatment started. can also mimic pheochromocytoma.9 There is also a Literature suggests the treatment of pseudopheochromo- description of a state of catecholamine excess indirectly cytoma consists of a combination of b- and a1-adrenergic resulting from a non-catecholamine-secreting tumor as blockade along with psychopharmacologic therapy.11 This pseudopheochromocytoma.10 More consistent with Kuchel’s strategy of dual adrenergic blockage in pseudopheochromo- original description of pseudopheochromocytoma, however, cytoma is supported by a study by Hamada et al., which Mann and co-workers used the term to describe paroxysmal demonstrated that the hemodynamic response to a valsalva in hypertension in the absence of biochemical catecholamine a population with pseudopheochromocytoma was much excess, but Mann11 also limited the description to the absence greater than that of the population with pheochromocytoma. of immediately identifiable panic or emotional distress. Hemodynamic monitoring implied a hyperactivity of both Consistent with the description by Mann, we will limit the the b- and a1-adrenergic receptor functions in pseudopheo- use of the term pseudopheochromocytoma in the context of chromocytoma. This is in contrast to the population with this discussion to describe a syndrome of unexplained true pheochromocytoma, which showed a blunted response paroxysmal hypertension without biochemical evidence of of both adrenergic systems due to desensitization associated catecholamine excess. Borrowing from that description, with chronic catecholamine excess. Administration of a paroxysmal hypertension differs from panic attack in that b- and a1-blocker to the population with pseudopheochro- there is a ‘clear relationship between blood pressure elevation mocytoma resulted in the normalization of hemodynamics and stress or emotional distress’ with panic attacks.11 and is thought to be the mechanism of symptom relief.12 Therefore, in addition to the otherwise unexplained paroxy- A less well-described and certainly perplexing aspect of sms of hypertension, we will specify that pseudopheo- pseudopheochromocytoma is the absence of overt emotional chromocytoma should exclude provocation from emotional distress yet reliance on psychopharmacologic therapy in distress as an underlying etiology. addition to adrenergic blockade. Our patient was seeing a In the case described here, paroxysmal hypertension was non-physician psychotherapist; however, she was not receiv- the predominant feature, and causes of paroxysmal hyperten- ing psychopharmacologic therapy. She did admit to psycho- sion with respect to catecholamine excess are presented in logical stressors such as a history of abuse, starting a new Table 3. Several of these etiologies were ruled out in our business, and fear of failure on behalf of her children, patient by the medical history, laboratory, and imaging however, she adamantly denied overt panic attacks or studies. Although she did not have a formal sleep study, she emotional distress preceding her attacks. Mann11 did identify did not have a history or physical exam suggestive of sleep repression of emotions, however, as a common feature of apnea. As she was evaluated for catecholamine excess both patients included in his case series. In this context, during and between hypertensive crisis, paroxysmal hyper- antidepressants and anxiolytics are aimed at treating a tension from catecholamine excess states as listed in Table 3A possible subclinical psychological disorder that predisposes was ruled out. A differential diagnosis for paroxysmal a certain population to these paroxysms of hypertension. hypertension without catecholamine excess could be sum- There is only anecdotal evidence regarding the type or marized in Table 3B. She adamantly denied preceding anxiety duration of this aspect of therapy, but resolution of symptoms with treatment often occurs in a short period of time in this selected population, as in our patient. After an Table 3 | Paroxysmal hypertension and catecholamine excess 18-month history of new onset, unprovoked paroxysmal states hypertension treated with several other agents to the point of A. Paroxysmal hypertension associated with plasma or urinary hypotension between attacks, ultimately only the combina- catecholamine excess Pheochromocytoma tion of relatively low-dose b-blockade, a1-blockade, and an Obstructive sleep apnea antidepressant produced a rapid and complete resolution of Anti-Parkinsonian drugs her symptoms in the absence of any change in other Cocaine use parameters such as her alcohol intake or psychosocial Baroreflex failure stressors. B. Paroxysmal hypertension in the absence of biochemical catecholamine excess SUMMARY Anxiety state (panic attack) In conclusion, clinicians should recognize secondary causes Thyrotoxicosis Pseudopheochromocytoma of paroxysmal hypertension specifically with regard to the Alcohol withdrawal patient suspected of having pheochromocytoma. The absence Carcinoid syndrome of a detectable catecholamine excess state in cases of

534 Kidney International (2008) 74, 532–535 J Hunt and J Lin: Paroxysmal hypertension in a 48-year-old woman the renal consult

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