FERE: Fractional excretion of random electrolytes

Magnesium:

• 142 controls: 1.8% (range 0.5-4%)
• 74 hypomagnesemic
• Extra-Renal origin 1.4% (range 0.5-2.7%)
• Renal origin 15% (range 4-48%)
• Authors conclusion: >4% per cent is indicative of inappropriate renal magnesium loss

Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia.

Potassium

• 312 normal subjects: 8% (range 4-16%)
• 84 hypokalaemic patients
• Extra-renal origin: 2.8% (range 1.5-6.4%)
• Renal origin: 15% (range 9.5-24%)
• Authors conclusion: >6.5% per cent is indicative of inappropriate renal potassium loss

Fractional excretion of potassium in normal subjects and in patients with hypokalaemia.

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.

Highest TTKG with hypokalemia

Patient with a lifelong history of hypokalemia. He came to me for a second opinion, his previous nephrologist had been nudging up his potassium dose on every visit and the patient was now on 70 mEq of KCl daily and was getting uncomfortable with endlessly increasing doses of potassium.

At the time I saw him these were his labs (he had decreased his potassium supplementation to 20 mEq/day):

• Blood
• sodium: 128
• glucose: 90
• potassium: 2.8
• Creatinine: 0.9
• BUN: 11
• Magnesium: 1.8
• Calculated osmolality: 265
• Urine 
• sodium: 135
• potassium: >100
• Osmolality: 637

Trans-tubular potassium gradient: 14.9. That's crazy high for a patient with hypokalemia, one should expect it to be less than 2 for hypokalemia of extra-renal origin, and only 7 or 8 for hypokalemia from hyperaldosteronism. Halperin et al. were not able to get the TTKG that high even when they took normokalemic patients and doped them with fludrocortisone and 50 mEq of oral potassium. 

And that 14.9 is assuming the urine potassium is 100, our lab doesn't do serial dilutions so who knows what the actual potassium is? 120? 140?

I'm still waiting for the renin and aldo but I smell some Bartter's

Hypokalemia and rhabdomyolysis

Hypokalemia can induce rhabdomyolysis. The purported mechanism is that hypokalemia antagonizes one of the natural causes of exercise induced vasodilation. Normally, during exercise muscles release intracellular potassium causing local pockets of hyperkalemia which triggers vasodilation and increases perfusion to the active myocytes. Total body potassium depletion and hypokalemia decrease local hyperkalemia preventing the vasodilation which results in tissue hypoxia and rhabdomyolysis.

 In The Fluid and Electrolyte Companion we illustrated it thusly:

I remember thinking how funny it was that we used bowling to represent exercise (though we did slide in those runners behind the bowler).  Oh clipart, how much nerdtainment you have given me.

This past week-end one of my patients experienced this. He is a high school student who loves to fish. He has congenital type 2 RTA, so is predisposed to hypokalemia. The exercise that triggered his rhabdo:  fishing. He presented to the ER following a day of fishing with complaints of muscle cramps and weakness. His potassium was reported as less than 2, with CPKs in the 800 range.

One of the unexpected consequences of the rhabdomyolysis was that his cramping continued after the potassium was corrected. In fact, it was actually much worse muscle spasm and tetany of the hands. Turns out, this second round of neuromuscular symptoms weren't due to hypokalemia but rather rhabdomyolysis induced hypocalcemia. He had a normal total calcium and a low ionized calcium. The muscular symptoms responded to a gram of IV calcium gluconate.

Potassium Chapters (Chapters 17-19)

17. Introduction to Potassium

17 Introduction to Potassium

18. Hypokalemia

18 Hypokalemia

19. Hyperkalemia

19 Hyperkalemia

Fluid and Electrolyte lecture at Providence from Friday

Third in the series of interesting fluid and electrolyte cases.

I would add a slide on where I was going in potassium before the anorexia section.

SlideSpace botches the torn paper frames I used through out the lecture so if you have Keynote, download and look at the native file.

Here is a link to the Keynote file.

Electrolyte Vignette

View more presentations from Joel Topf. (tags: alcoholism magnesium)

Internal Medicine Board Review: Fluids, Electrolytes and Acid Base

The chief resident at Providence asked me to do a board review class for the third-years. They have small sessions weekly (?) in the physician lounge. This afternoon we went over fluids, electrolytes and acid-base. We did the first 14 questions. Seems like it went pretty well.

Board Review Questions and Answers

Fluid and Electrolyte lecture at Providence from Tuesday Dec 16

I did a lecture at Providence last week.

I was scheduled to just give a electrolyte lecture without any further guidance. I pulled out two interesting cases I had seen in the last few weeks. Both patients have a non-anion gap metabolic acidosis, but one is hypokalemic and the other is hyperkalemic.

Here is the native Powerpoint files for you to use or edit.

Here is the SlideShare for online viewing

Non-anion gap Metabolic Acidosis (NAGMA)

View SlideShare presentation or Upload your own. (tags: acid base)

Great cases on call

I'm running the on-call gauntlet.

I was on call Sat and Sun December 6,7

Sat December 13

Sat and Sun December 20,21

Thursday through Sunday December 25-28

four straight week-ends, with Christmas thrown in for the Jew. Ughh.

That said this week-end has had a few great cases:

• IgM Cold-agglutinin hemolytic anemia in need of plasmapheresis.
• Fluconazole induced hyperkalemia
• Urinary obstruction induced electrogenic type 1 RTA (Hyperkalemic variety of type 1 RTA)
• Primary hyperaldosteronism induced hypertensive emergency
  

I'll elaborate on some (all) of these cases in the next few days.

Happy holidays

Patient with a Liddle problem

The Set Up

42 year old African American woman presents with muscle weakness and palpitations. Her blood pressure is 180/110. Her hypertension has been documented since age 16.

Her sister has a history of hypokalemia and hypertension. Three of her six kids, all of which are younger than 20 have hypertension.

Na 144
Cl 96
BUN 14

Photo: Creative Commons/Paleontour

K 2.7
Bicarb 42
Cr 0.8

ABG
pH 7.54
pCO₂ 51
paO₂ 97

Step one

What is the primary acid-base disturbance.
pH is elevated, so its an alkalosis. The pH, pCO₂ and HCO₃ are all going up (same direction) so it is a metabolic condition. Metabolic alkalosis.

Step two

Is compensation appropriate.
To find the target pCO₂ add two thirds of the delta bicarb to a normal pCO₂ of 40 mmHg.

Her bicarb is 42, and the delta (42 – normal bicarb of 24) = 18.
Two thirds of 18 is 12.
40 + 12 = 52 mmHg.

Actual pCO₂ is 51, so we are in the house, pCO₂ is appropriate for a serum bicarbonate of 42, no second primary disorder affecting compensation.

Step three

What is the differential of hypokalemia, metabolic alkalosis and abnormal blood pressures?

Hypokalemnia and metabolic alkalosis is an important pattern. The first concept that medical students invariably want to lean on is the intracellular exchange of hydrogen and potassium. When there is hypokalemia, potassium flows from the cells. To maintain electroneutrality hydrogen goes into the cells. The certainly is operating in these cases, however a model that looks at changes in total body potassium is much richer.

The reason that metabolic alkalosis and hypokalemia can walk together is that they both are responces to hyperaldosteronism. The increased aldosteronism can be primary, secondary or unusual.

• Secondary hyperaldosteronism. Patients with GI losses, diuretics or other causes of volume depletion will upregulate their aldosterone. Aldosterone will fight the volume depletion by reabsorbing sodium in the principle cells, flowing down its concentration gradient through the eNAC. Aldosterone increases the number and activity of the eNAC channels (it also increases the number and activity of the potassium channels and the Na-K-ATPase).
• Volume deficiency
• Renal artery stenosis decreases renal blood flow and induces a secondary hyperaldosteronism
• Primary hyperaldosteronism. This is major cause of hypertension. Patients can have metabolic alkalosis and hypokalemia. If your patient has hypokalemia and alkalosis, definatly pursue primary hyperaldo, but do not rule out primary hyperaldo if you don't have the electrolyte abnormality. Most patients with pimary hyperaldo do not have the typical electrolytes.
• Unusual: one conditions to remember that cause metabolic alkalosis and hypokalemia:
• Liddle syndrome. Patients have a mutation at 16p12 that encode the beta and gamma subunits of the eNAC. The eNAC is no longer sodium selective and is always open. The sodium reabsorption causes hypertension. The eNAC channel also increases potassium and hydrogen secretion.
• The functional opposite of Liddle syndrome is Pseudohypoaldosteronism type 1. Here mutations to the alpha, beta or gamma subunits results in resistance to the effects of aldosterone. Patient have sodium wasting and hyperkalemia. There is an autosomal recessive and autosomal dominant form.
• Licorice and SAME (Syndrome of Apparent Mineralocorticoid Excess) The structure of cortisol and aldosterone are almost identical and the mineralocorticoid receptors in the principle cells are unable to differentiate between these molecules. This means that cortisol can activate the mineralocorticoid receptors. This is made worse by the fact that cortisol typically is found at concentrations a 1000-fold higher than aldosterone. To prevent cortisol from acivating the mineralocorticoid receptors, cortisol is rapidly metabolised by 11-beta-hydoxysteroid dehydrogenase. If this enzyme is absent (SAME) or inhibited (licorice ingestion) you can get wildly up-regulated mineralocorticoid activity with simultaneous suppression of aldosterone.

1. Sodium is reabsorbed through the ENaC. Sodium moves
   down its concentration gradient.
2. The movement of sodium is electrogenic and results in
   a negative charge in the tubule.
3. Chloride in the tubule can be reabsorbed paracellularly.
   The more chloride that is reabsorbed the less potassium
   is secreted.
4. Potassium flows down an electrical and chemical gradient into the tubule.

Step four

The family history shows first degree relatives with a similar condition. This suggestes autosomal dominant transmission. This is consistant with Liddle syndrome.

Step five

Next steps in the diagnosis. Though the genetics are suggestive of autosomal dominant transmission, Liddle Syndrome is very uncommon while primary hyperaldosteronism is relatively common. A serum aldosterone level will separate these patients neatly. In Liddle Syndrome the aldosterone is suppressed, while in primary hyperaldosteronism it is up regulated. Genetic testing is available to confirm the diagnosis.

See these posts at the Renal Fellow Network for additional information.