We've got one! Finding a functional adrenal adenoma

A year ago, a slender, 40 year old, white female presented to my clinic with new onset elevated blood pressure. The hypertension was discovered during a routine visit for a minor injury. The family practitioner refused to believe the vitals and kept having the patient return for follow-up visits before resigning himself to the diagnosis. Surprisingly, this otherwise healthy woman, was resistant to multiple medications. He began to suspect a more sinister diagnosis and initiated a work-up for secondary hypertension and referred her to me.

The initial work-up showed a aldosterone of 16 but the renin was not done. She also had modestly elevated metanephrines, but not high enough to suggest a pheochromacytoma. Her blood pressure typically ran 140-160/100 with labetalol 100 mg bid, but she admitted to being forgetful regarding her medications.

One of the findings that stood out for me was the hypokalemia on the initial labs

We repeated the renin-aldo ratio and did a EKG. Unfortunately she had LVH. For me, this ruled out white coat syndrome. The demonstration of end-organ damage also helped the patient see that this condition was "real" and after that she was compliant with the medical therapy.

The repeat Aldo was only 3 with a fully suppressed renin at 0.15. This is an aldosterone-renin ratio (ARR) of 20, however, I was taught a low total aldosterone ruled this diagnosis out. In other words, one needs an elevated aldosterone, not just a suppressed renin to make the diagnosis of primary hyperaldosteonism. This always made sense to me but the Endocrine Society states that this is not always true and questions the requirement for a high aldosterone:

Against a formal cutoff level for aldosterone are the findings of several studies. In one study, seated plasma aldosterone levels were less than 15 ng/dl in 36% of 74 patients diagnosed with PA after screening positive by ARR defined as more than 30 and showing failure of aldosterone to suppress during fludrocortisone suppression testing (FST), and in four of 21 patients found by AVS to have unilateral, surgically correctable PA.

Her potassium remained low at 3.1 despite potassium supplementation. She was breast feeding at the time so we did not use an ACEi or ARB and were successfully treating her blood pressure with a combination of nifedipine XL and labetalol.

The low aldosterone appeared to rule-out primary hyperaldo but with the unexplained hypokalemia I ordered a third ARR and hit pay-dirt

An ARR of close to 300 with a sky-high aldosterone of 29. Remember, when you calculate the aldosterone-renin ratio make sure the units are correct:
  • aldosterone in nanograms per deciliter
  • renin measured as plasma renin activity (PRA) in nanograms per milliliter per hour
With a positive ARR, the endocrine society recommends a confirmatory test. There are four recommended tests, all of which are variations on attempts to suppress endogenous aldosterone via sodium loading or fludrocortisone suppression. I did not do this. I feel that the critical diagnosis to make is the functional adenoma that is surgically curative. Whether the patient has bilateral hyperplasia or simply aldosterone driven hypertension that doesn't meet the criteria for primary aldosterone is not important to me because I'm going to treat both of those conditions identically, with spironolactone or eplerenone.

So we proceeded with the work-up for a functional adenoma and sent her for a CT scan. We found a 1 x 2 cm left adrenal mass.

Here is where it gets tricky. This sounds like a functional adenoma, however functional adrenal adenomas are rare diagnosis, and even in the presence of documented hyperaldosteronism, non-functional incidentalomas are too common (0.35-5%) to assure that a CT finding of an adrenal mass represents a functional adenoma. Following a CT scan, you can neither rule-out nor rule-in the diagnosis of a surgically correctible functional adenoma. Patients still need to get adrenal vein sampling. Here is the experience from University of Texas Southwestern:
Twenty patients had unilateral CT abnormalities, and 14 (70%) of them lateralized to the same side (concordant). Of the remaining 6 patients with unilateral CT abnormalities (3 left and 3 right), 1 patient each lateralized to the opposite side and 2 patients each had bilateral hypersecretion. Only 5 of 15 patients (33%) with bilateral CT abnormalities showed concordant bilateral aldosterone hypersecretion. The other 10 patients (67%) demonstrated unilateral hypersecretion. Of the 5 patients with normal-appearing adrenal glands on CT, 1 patient each lateralized to 1 side, and the other 3 patients had bilateral hypersecretion.
The authors did not provide a 2x2 table to determine sensitivity or specificity (insert rant regarding surgical literature here) so I put one together. This is how I interpreted the data above:

  • Positive test: 20 with unilateral findings, 14 true positives and 6 false positives (I considered the CT scan identifying the wrong affected adrenal as being a fail)
  • Negative test: 15 patients with bilateral findings, 5 were true negatives and 10 were false negatives
  • Negative test: 5 patients with normal adrenals, 2 lateralized, false negatives and 3 true negatives
The two-way table looks like this:
What? You're still using Epocrates' medical
calculator? Don't be a tool, get a tool, MedCalc

It should be apparent that a CT scan looks truly terrible at diagnosing a functional adenoma. A negative predictive value of only 40%. Ughh! Note: these numbers assume the adrenal vein sampling is a valid gold-standard.

We sent her for adrenal vein sampling to see if the aldosterone secretion lateralizes. It did with a 20-fold increase in aldosterone on the left side. Because aldosterone levels can be unreliable due to dilution and technique, it is recommended that an adjusted aldosterone (aldo/cotisol) exceed the contralateral adrenal by three fold. In our case, it was 10-fold.

She went for an laparoscopic left adrenalectomy and is now normotensive off all medications.

The endocrine society had published consensus recommendations on screening, diagnosis and treatment of primary hyperaldosteronism. I love it when important articles are available in PDF for free.