Tag: aldosterone

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Metabolic alkalosis and hypokalemia go together like Phineas and Ferb

This is one of my favorite lectures. It starts with Izzy getting fired on Grey’s Anatomy to the metabolic consequences of crack cocaine in dialysis patients to the imaginary monogenic diseases of Ethan Hawke and Denzel Washington. Metabolic alkalosis is a topic that is rarely taught at all. This lecture goes deep tying metabolic alkalosis to potassium handling (as does the kidney). The lecture covers a lot of useful kidney physiology. In addition to metabolic alkalosis it covers some of the salt wasting nephropathies and monogenic causes of hypertension.

Keynote | PDF

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Aldosterone escape versus Aldosterone breakthrough

Fluid and electrolyte deity, Robert Schrier,  had an interesting editorial in Feburary’s Nature Reviews: Nephrology (yes, I’ve gotten a little behind in this blogging business).

Escape versus breakthrough refere to completely different and unrelated concepts related to aldosterone.

  • Aldosterone breakthrough occurs following administration of an ACEi or ARB. ACEi block the conversion of angiotensin I to angiotensin II. The decrease in angiotensin II lowers aldosterone. Angiotensin receptor blockers prevent angiotensis II from from binding receptors through out the vasculature but including the adrenal gland where it prevents aldosterone release. At least that is the plan. In reality about 30-40% of patients given ACEi or ARBs have only a temporary decrease in aldosterone and then after a few weeks, aldosterone returns to pre-treatment levels.  

  • Aldosterone escape is a physiologic phenomenon that occurs with hyperaldosteronism. Aldosterone initially decreases urinary sodium increasing sodium retension contributing to hypertension. This does not result in edema because the sodium retention is short lived. After a short time urinary sodium returns to normal through a process called aldosterone escape. There are two processes that account for this:

    1. Pressure natriuresis. Increased blood pressure decreases distal sodium resorption. The exact mechanism of pressure natriuresis is unknown, it is thought to be mediated by hydrostatic forces. Increased blood pressure is transmitted to the peritubular capillaries, so the resorption of solutes must overcome an elevated hydrostatic pressure gradient. In the face of this increased gradient, sodium resorption falls.
    2. Decreased proximal sodium resorption. Volume expansion decreases proximal sodium reabsorption and increases sodium delivery to the distal nephron and overwelms the aldosterone induced sodium resorption.

The implications of aldosterone escape is that primary hyperaldosteronism does not cause edema. It also explains the delay in hypokalemia found with primary hyperaldosteronism. Aldosterone stimulates potassium excretion but hypokalemia is a late finding in primary hyperaldosteronism. The increased potassium excretion occurs with aldosterone escape when the increased sodium delivery (decreased proximal absorption, i.e. escape) occurs with the increased aldosterone levels.

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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.