hypokalemia and metabolic alkalosis

A few years ago I was talking one of my mentors at Kidney Week, John Asplin. He mentioned

that he taught an integrated lecture on metabolic alkalosis and hypokalemia. I thought this was an inspired idea.

Teaching separate classes on both subjects results in a lot of overlap because the renal mechanisms for both disease are the same, this means that many of the diseases that cause one, also cause the other.

Additionally hypokalemia can cause metabolic alkalosis and metabolic alkalosis can cause hypokalemia, so it makes sense to teach both of these conditions in an integrated lecture.

Lastly, teaching each electrolyte individually in isolation from each other is a missed opportunity. One can only appreciate the beauty of electrolyte physiology when one understands how each electrolyte fits together and how abnormalities in one is associated and affects all of the other electrolytes.

Unfortunately, I botched the lecture. I gave this lecture for the first time for the Oakland University Beaumont Medical School this past August. I knew it didn't go too well, but this week I received the class feedback. Overall my statistical evaluations were excellent but when I read the comments the students were jackals. They savaged this lecture.

Timing was on my side, I was scheduled to give this lecture the day after I received feedback. I'm not done tweaking it but what I did for my Tuesday lecture was add more connective tissue between the concepts, and fill in with some additional summary slides.

Right now, I'm using it as a lecture to follow-up my potassium lecture, but at OU the students didn't have any baseline potassium knowledge. In order for this lecture to work the students must already understand the basics of potassium, especially the central role that renal potassium handling has in potassium homeostasis. Hopefully I will be able to negotiate another hour into the GU schedule for this lecture.

My next plans for this lecture is to cut out a lot of the opening slides. The purpose of those slides is to quickly move from introducing potassium and hypokalemia to getting to the truth that hypokalemia is almost solely a disease of increased renal losses.

I want to add a slide about disease opposites:

• Pseodohypoaldosteronism type 1 and Liddle syndrome
• Godon's syndrome and gittleman's syndrome
• Adrenal insufficiency and AME

I want to add some slides on how hypokalemia causes (specifically, maintanes) metabolic alkalosis and then how metabolic alkalosis causes hypokalemia.

Here is the lecture (Keynote version | PDF)

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.