The hypertension seemed under control, but now the patient had muscle cramps, throbbing headaches, thirst, and nocturia.
For the past several months, Ms. F, a 56-year-old African American, had been suffering from profound generalized fatigue and weakness with increasing muscle cramps of her hands and legs. In addition, she was increasingly thirsty and urinating more frequently, often waking to urinate during the night. Ms. F noted intermittent frontal headaches at least once or twice a month, throbbing in nature, lasting hours, and self-remitting; there was no associated aura or blurred vision. She denied any stressors, nausea, vomiting, fever, chest pain, shortness of breath, or abdominal pain.
HISTORY
The patient's only significant medical history was recently diagnosed mild hypertension and obesity. Her mother had had a mastectomy for breast cancer but was alive and in good health at the age of 81. Ms. F's only brother had diabetes mellitus.
Heterosexual and single, Ms. F lived alone. Her last sexual activity had occurred several years ago. She had smoked one to two cigarettes per day for the past 40 years, enjoyed occasional social drinking, and had no history of drug abuse. She denied licorice ingestion. Her only medication was hydrochlorothiazide 25 mg once daily; she had no known drug allergies.
WORKUP FINDINGS
Vital signs were temperature 98.3°F, pulse rate 76 beats per minute, respiration rate 16 breaths per minute, BP 165/85 mm Hg. At 5 ft 2 in tall and 220.5 lb, she was obese (BMI 40 kg/m2). The patient was in no acute distress. Full range of motion was observed in all joints, but some decrease in deep tendon reflexes was noted in both upper and lower extremities. The rest of the exam was unremarkable.
The only noteworthy lab results were a low potassium (3.3 mEq/L) and a slightly elevated bicarbonate level (31 mEq/L). Further review revealed that Ms. F had had hypokalemia for several months, but it had somehow been missed on earlier routine lab results. Her total cholesterol was 247 mg/dL, LDL 140 mg/dL, triglycerides 154 mg/dL, and HDL 66 mg/dL. On urinalysis, no leukocytes, nitrites, or glucose explained her polyuria and nocturia. The patient's hydrochlorothiazide was stopped. Electrolyte studies repeated one week later showed that her potassium remained low at 3.2.
Supplementation tended to normalize her potassium but did not markedly improve her symptoms. Hydrochlorothiazide/triamterene (Dyazide), a combination diuretic/potassium-sparing diuretic, seemed to control her BP, but her potassium remained low.
OUTPATIENT COURSE
Four weeks later, Ms. F's fatigue and weakness persisted. On Doppler exam, no renal artery stenosis explained her hypertension. After Ms. F's medications had been stopped again, analysis revealed increased aldosterone levels and decreased renin activity. A 24-hr urinary aldosterone and urinary potassium were ordered. Serial plasma aldosterone (PA) and plasma renin activity (PRA) levels were ordered over several days. During this period, vital signs, especially BP, were monitored in the clinic every two days. Ultimately, her potassium was near-normal at 3.5. PA levels, however, were consistently elevated at >20 ng/dL (range 20-35, depending on time of day and position of blood draw). With PRA levels at 1.4-1.9 ng/mL/hr, Ms. F had a PA-to-PRA ratio >20, signifying primary hyperaldosteronism. The patient also had a mildly elevated 24-hr urinary potassium (41 mEq/ day) and a high-normal 24-hr urinary aldosterone (12 µg/day).
Abdominopelvic CT found both adrenals to be within normal limits but could not differentiate on cuts <3 cm; hence adrenal hyperplasia remained a possibility. The endocrinologist reported a high suspicion for primary hyperaldosteronism and recommended spironolactone 30 mg/day for four weeks, with a follow-up CT scan as well as aldosterone and renin determinations in three months. Over the next four to six weeks, Ms. F's weakness and muscle cramps improved markedly, and her aldosterone and renin levels returned to normal. Because she was doing so well clinically, the repeat CT was scheduled for one year later.
CONN'S SYNDROME
Primary hyperaldosteronism, also known as “Conn's syndrome,” causes the kidneys to retain sodium and excrete potassium. Patients exhibit hypertension, hypokalemia, and low PRA. Primary hyperaldosteronism occurs in 0.2%-5% of people diagnosed with hypertension and is more common in women than men by a ratio of 2:1. Some reports suggest a higher prevalence in African Americans. Peak incidence occurs in the third to sixth decades of life.
Possible causes of primary hyperaldosteronism include unilateral aldosterone-producing adenoma (more common in females and responsible for 80% of all cases) and bilateral adrenal hyperplasia (more common in males and responsible for only 20% of all cases). Adrenal carcinomas occur in <2% of all patients suspected of having Conn's.
More than 80% of patients with Conn's syndrome are asymptomatic. Muscle weakness, cramps, and marked paralysis can be attributed to hypokalemia. Carbohydrate intolerance can lead to polyuria and polydipsia. Mild to severe hypertension is responsible for occasional nocturia, frontal headaches, and occasionally peripheral neuropathy.
The preferred screening method is to measure early morning PRA and PA levels with the patient resting for 30 minutes in a supine or sitting position. A high PA level (>15 ng/dL), a low PRA (<1 ng/mL/hr), and a high PA-to-PRA ratio (>20) is highly diagnostic. Positive screening should be followed by a 24-hr urine aldosterone determination; a urinary aldosterone level >14 µg/day is confirmatory.
Most antihypertensives, especially diuretics and spironolactone, must be stopped prior to testing. Alpha blockers, e.g., doxazosin (Cardura) or terazosin (Hytrin), do not interfere with testing; calcium channel blockers and clonidine may also be used to control resistant hypertension during the testing. The duration of antihypertensive-agent cessation prior to testing is six weeks for spironolactone, four weeks for diuretics, two weeks for ACE inhibitors, one week for sympatholytics, and one week for calcium channel blockers.
TREATMENT
Underlying cause determines treatment. Laparoscopic adrenalectomy after four to six weeks of spironolactone therapy (e.g., 300 mg/day) is the treatment of choice for adenoma. Of patients who undergo adrenalectomy, 80%-90% experience complete resolution or marked improvement of their hypertension. Quality of life is generally good, although some patients may not be able to tolerate spironolactone treatment.
In adrenal hyperplasia, spironolactone or amiloride is generally sufficient to reverse the hypokalemia and control the BP. Because long-term spironolactone causes impotence and gynecomastia, this agent is generally used for women, while amiloride is used for men. With persistent hypokalemia, cardiac arrhythmias are a serious complication.
Dr. Shah is a family physician with Kaiser Permanente in Fontana, Calif.