Lecture 18: Hypokalemia Flashcards
What rarely ever causes hypokalemia?
Getting hypokalemia WITHOUT medication
Occurrence of hypokalemia in a “healthy” adult without taking medication is SO RARE that the presence of an underlying disorder should be suspected and a diagnostic workup should be initiated
Within the ICF, where is the majority of the body’s potassium stored?
In the muscle
ECF = 3.4-4.6 mEq/L ICF = 150 mEq/L Stool = 10 mEq/day of K Sweat = 5 mEq/day of K So if you have diarrhea or sweat a lot, you can lose a significant amount of K still
What are the common causes of hypokalemia?
- Changes in external K balance
a. inadequate intake (rarely the case)
b. increased loss through GI, Renal, sweat, dialiss - Redistribution (increased entry into cells)
a. causes only transient hypokalemia
Balance vs Redistribution
Most of the times it is due to loss through GI tract and kidney
What is one thing to keep in mind about patients who have excessive K loss through sweat?
Patient losing that much K in sweat is most likely in a hot, humid environment
Therefore, hypokalemia is secondary to primary volume depletion
-it is the volume depletion and the subsequent hyperaldosteronism that is causing maintenance of hypokalemia (rather than losing so much of the stuff through sweat)
What are the key characteristics of hypokalemia due to inadequate intake?
Very rare but can be a contributory factor
Usually associated with defect in renal conservation
Specific causes include
i. Tea and toast diet
ii. anorexia nervosa
iii. alcoholism
With starvation, body K stores are depleted but tissue breakdown will release K into the ECF, which will mitigate hypokalemia
What are the drugs that cause hypokalemia due to transcellular potassium shifts?
- Beta-2 adrenergic agonists
i. Epinephrine (exogenous or endogenous) Catecholamines
ii. Bronchodilators - Insulin
What is the mechanism through which epinephrine leads to hypokalemia?
Epinephrine binding to beta-2 adrenergic receptors upregulates Na/K activity
Increases insulin release
Rudnick’s response: mechanism is quantitative but it seems that there is greater beta than alpha activity (former increases insulin release while latter inhibits insulin release)
What are the types of bronchodilators that are beta-2 adrenergic agonists?
- Albuterol
- Ephedrine
- Isoproterenol
What happens to a hypokalemic patient who has a MI?
The MI can lead to release of epinephrine, a beta-2 adrenergic agonist which will upregulate insulin and exacerbate hypokalemia
Why is there a higher risk of ventricular arrhythmias and sudden death in hypokalemic patients?
Endogenous catecholamine release during MI increases ventricular irritability by increasing Na/K activity and further decreasing serum potassium level
What is the effect of insulin on K?
Insulin promotes entry of K into the skeletal muscles and hepatic cells
MoA: Increases Na/K ATPase activity
What are other causes of hypokalemia of transcellular potassium shifts?
- Alkalosis
- Hypokalemic periodic paralysis
- Rapid cell growth (things that produce new cells)
i. reaction of megaloblastic anemia (folic acid, vitamin B12)
ii. Parenteral hyperalimentation (when you don’t give someone K on total parenteral nutrition)
iii. Granulocyte macrophage colony stimulating factor (GM-CSF)
Why does alkalosis promote K entry into the cell and hypokalemia?
Metabolic and respiratory alkalosis will lead the body to excrete more H+ from ICF to ECF
H+ movement is counteracted by K movement, so for every H that moves out, there is a K that moves in
What are the key characteristics of hypokalemic periodic paralysis?
Rare disorder with two variants
1. autosomal dominant manifested in 10-20 year olds
2. acquired trait in Asians from 30-40 and associated with thyrotoxicosis
Attacks involve proximal skeletal muscles and are precipitated by large carb ingestion (possibly because of insulin release)
What are the most important systemic causes of hypokalemia?
- Catecholamines (epinephrine)
- Insulin
- Alkalosis
- Treatments that result in production of large numbers of cells (parenteral nutrition, folic acid administration for megaloblastic anemia)
- that is because greater cell to serum ratio, so more K from serum is taken up
What is pseudo hypokalemia?
When serum K levels decrease AFTER it is drawn from the patient
Seen in myeloid leukemia
These neoplastic are metabolically active and take up K from serum after blood removal
What are the causes of hypokalemia due to increased stool potassium loss?
- Diarrhea (any etiology)
- laxatives
- Villous adenoma
- Uterosigmoidostomy
- Sodium polysterene sulfonate
- Geophagia (ingestion of clay because clay binds K)
What is the K concentration in stool water? Significance?
80-90 mEq/L
Normally, there is minimal water in your stool normally (so it decreases amount to 10 mEq/L)
But if you have too much water due to diarrhea, you can get hypokalemia)
What is ureterosigmoidostomy?
A surgical procedure in which the ureter is implanted into a segment of sigmoid colon, thus creating a new primary bladder for patients
Urine secreted to sigmoid colon will get Na/Cl reabsorbed but GI epithelium will secrete K
What is sodium polysterene sulfonate?
Aka Kayexelate
A cation exchange resin commonly used to treat HYPERkalemia
Given orally or by enema
Sodium ions released by the resin are replaced by potassium secreted into the bowel lumen, resulting in net loss of K
Lecturer asserts that this may be due to the sorbitol that is bundled up with sodium polysterene sulfonate
What is the primary determinant of urinary K excretion?
The distal tubule
What are the factors that lead to enhanced distal tubular K secretion?
- Increased distal tubular Na delivery and flow
- Increased mineralocorticoid activity
- Increased delivery of poorly reabsorbable anions
- Acid-base balance
- Magnesium depletion
What happens if you have low magnesium in the distal tubule?
If you have low magnesium, a lot of K is going to come out of the ROMK channel
What is the ROMK channel?
Renal outer medullary potassium channel
What are the causes of hypokalemia due to increased RENAL potassium loss?
- Diuretics
- Acid-base disorders
i. Distal RTA
ii. Proximal RTA
iii. metabolic alkalosis
What are the diuretics that lead to hypokalemia?
- Acetazolamide
- carbonic anhydrase inhibitor
- associated with hyperchloremic metabolic acidosis (normal anion gap)
- Loop diuretics
- Thiazides
- Osmotic diuretics
What is the mechanism of hypokalemia with diuretics?
- Increased Na and H2O to collecting tubule which creates favorable electrical gradient for K secretion
- increased flow due to diuretics leads to hyperaldosteronism and aldosterone increases potassium secretion
- Diuretics can induce metabolic alkalosis
What is the mechanism of hypokalemia with renal tubular acidosis?
Increased distal Na delivery and flow + secondary hyperaldosteronism (for both type I and II) For distal (Type I) RTA, defect H ion secretion promotes Na/K exchange For proximal (Type II) RTA, no reabsorption of bicarb = more bicarb in distal tubule = more K secretion
What are the features of diuretic induced hypokalemia?
K loss occurs during first 2 weeks until new lower steady state is established
-steady state wont be altered until there is a change in diuretic dose/K intake
Magnitude of hypokalemia ~ diuretic dose ~ Na content of diet
Associated with mild-moderate metabolic alkalosis
What should one suspect with unexplained hypokalemia and metabolic alkalosis?
Diuretics
Bartter Syndrome
How does increased bicarb concentration in the distal tubule affect K secretion?
More bicarb distally = more K secretion because bicarb is a poorly absorbed ion
What is the DDx of hypokalemia?
Bartter syndrome
Diuretics
Hypokalemia due to renal loss of potassium
What are primary causes of hyperaldosteronism that leads to hypokalemia?
- excessive mineralocorticoid effect with HTN
i. Primary hyperaldosteronism due to adrenal adenoma or bilateral adrenal hyperplasia
ii. Apparent mineralocorticoid excess (AME) syndrome
What causes apparent mineralocorticoid excess (AME) syndrome?
Acquired by eating licorice
Acquired by eating Carbenoxolone
Inherited = 11 beta-hydroxysteroid dehydrogenase-2 deficiency
What is at the top of your DDx if you get a patient with HTN, hypokalemia, K supplements and NO diuretic use?
Primary Aldosteronism
What is the screening test used to diagnose primary aldosteronism?
Ratio of plasma aldosterone: plasma renin
If aldosterone:renin is 30:1, you know patient has hyperaldosteronism AND plasma aldosterone has to be greater than 20 ng/dL
-if aldosterone level is not high, but renin levels are just very low (to make ratio 30), then it is not hyperaldosteronism
What is primary aldosteronism?
The most common cause of secondary HTN 1-2% of HTN population 60% due to adenoma (pictured on right) 40% due to bilateral adrenal hyperplasia Serum K may be normal in up to 40% of patients
What are the key characteristics of apparent mineralocorticoid excess
Syndrome (AME)?
- Cortisol binds avidly to aldosterone as to distal tubular MR
- plasma concentration cortisol»_space;> aldosterone
- Normally cortisol does not have mineralocorticoid activity because 11 beta-hydroxysteroid dehydrogenase-2 converts cortisol to cortisone (to inactivate mineralocorticoid)
- 11 beta-hydroxysteroid dehydrogenase-2 deficiency allows cortisol to act as a mineralocorticoid
Lab tests show normal levels of aldosterone despite high levels of aldosterone activity (which is surreptitiously stimulated by K)
AME can cause hypertension as well
How does cortisol act as aldosterone?
Cortisol can bind to mineralocorticoid receptor, but is normally prevented from doing so by 11 beta-hydroxy steroid dehydrogenase-2
-if there is a defect in the gene, then cortisol can act as aldosterone
Thus you get apparent mineralocorticoid excess syndrome (AME)
What are the characteristics of hyperreninism?
Can lead to hypokalemia
Renovascular HTN and malignant HTN can stimulate too much renin which leads to too much aldosterone
So is caused by renovascular and malignant HTN
What are the key characteristics of glucocorticoid remedial hyperaldosteronism (GRA)?
Autosomal dominant
Lab studies = low renin, high aldosterone, bilateral adrenal hgyperplasia, HTN and hypokalemia
Primary defect is in aldosterone synthase and 11 beta-hydroxylase
Characterized by aldosterone production in zona FASCICULATA rather than zona GLOMERULOSA
-thus aldosterone production is ACTH sensitive rather than angio II sensitive
Treatment: give patient glucocorticoids in order to decrease ACTH synthesis
What are the key characteristics of Liddle’s Syndrome?
Autosomal dominant
Mutations in ENaC in collectign duct, leading to activation of the channel
Activation of ENaC = unregulated and enhanced Na Reabsorption
More Na reabsorption = more K secretion from apical K channel
Lab values: low aldosterone and spironolactone does not ameliorate the disorder
What are the causes of secondary hyperaldosteronism?
- Primary salt-wasting nephropathies
2. Secondary salt wasting nephropathies
What are the primary salt-wasting nephropathies?
Defects that lead to hyperaldosteronism
- Bartter’s syndrome
- Gitelman’s syndrome
What are the secondary salt-wasting nephropathies?
Defects that lead to hyperaldosteronism
- Diuretics
- Acid-base disorders
i. distal and proximal RTA
ii. metabolic alkalosis
What is the MoA of Bartter’s Syndrome?
Blockage of Na transport in TAL
Defective transporter can be NKCC2, basolateral Cl channel or apical ROMK channel
Leads to sodium wasting
What are the characteristics of Gitelman’s Syndrome?
Defect in Na reabsorption in DCT
Defect is in NaCl cotransporter
Leads to sodium wasting
Sodium wasting then leads to increase of volume sensitive hormones like aldosterone
What are the characteristic findings of barters and gitelmans?
- hypokalemia
- urinary Na and K wasting
- metabolic alkalosis (due to aldosterone compensation)
- Elevated PRA (plasma renin activity) and serum aldosterone levels (secondary hyperaldosteronism)
- Magnesium depletion
What are the laboratory differences between Bartters and Gitelmans?
Bartter = TAL = where Mg and Ca is reabsorbed
In Bartters, there is increased loss of Mg and Ca due to reduction of lumen positive differential that normally drives paracellulary absorption of the two ions
-can lead to nephrocalcinosis
So Bartters = Hypercalciuria
In Gitelman’s however, impaired NaCl transport in DCT leads to hyperpolarization of cell and ENHANCED reabsorption of calcium
So Gitelmans = Hypocalcuria
What can cause severe magnesium depletion along with hypokalemia?
- Amphotericin B
- Cisplatinum
- Aminoglycosides
- Diuretics
- Alcoholism
- due to secondary hyperaldosteronism caused by loss of volume from vomitus
What is cisplatinum?
An anti-tumor agent
Can cause hypokalemia and Mg depletion
What are aminoglycosides?
Antibiotics that cause hypokalemia and Mg depletion
What is the mechanism of hypokalemia in magnesium depletion?
Mg deficiency associated with increased renal K excretion
Mg replacement prevents renal K wasting by decreasing K secretion in distal nephron
ROMK potassium channel can allow K to move both into and out of cell
If Mg replete in cell, Mg binds to ROMK preventing movement of K out of the cell
Thus, if you have no Mg, then there is nothing to block ROMK, so K moves out cell freely
0 mEq Mg = K efflux
1 mEq Mg = net K influx (since K stays within cell)
What are non-reabsorbable anions
that cause K renal wasting?
- Bicarb
- penicillin and penicillin analogues
- Beta-hydroxybutyrate (diabetic ketoacidosis)
Why is it important to exclude transcellular shifts (redistribution) first?
Because redistribution only causes transient hypokalemia
What are the clinical effects of hypokalemia?
- Cardiac changes
- Neuromuscular changes
- Endocrine changes
- Renal changes
What are the cardiac changes associated with hypokalemia?
- EKG changes = ST depression, T wave flattening and prominent U wave
- Ventricular arrhythmias
- Impaired cardiac contractility
Action potential mechanisms:
i. increased automaticity
ii. decreased conduction velocity
iii. shortened refractory period
Hypokalemia = hyperpolarization
= but also reduction on K permeability
= reduction of K permeability = shortened
Refractory period since the time in which
K is permeable in membrane is decreased
= thus you have increased automaticity
What are the neuromuscular manifestations of hypokalemia?
Hyperpolarization = muscle weakness, fatigue because impaired ability to depolarize
- constipation in the ileum
- Rhabdomyolysis
- weakness and paralysis
- ileus
What is intestinal ileus?
Disruption of normal propulsive ability of the GI tract
What are the endocrine manifestations of hypokalemia?
Decreased insulin secretion
Decreased organ sensitivity to insulin
-limited to mild glucose intolerance
Significance: can worsen condition of diabetics
What are the renal effects of hypokalemia?
- Polyuria and polydipsia (Nephrogenic Diabetes insipidus)
- Increased NH3 production that leads to Hepatic coma
- Metabolic alkalosis
- Na retention and HTN (mechanism uncertain)
- Chronic interstitial nephritis (hypokalemic nephropathy)
What causes polyuria?
Defect in cellular response to ADH
How does one get increased NH3 production and hepatic coma from hypokalemia?
Potassium is important in regulating ammonia secretion
Increased Potassium secretion = increased intracellular acidosis = increased ammonia production
No potassium intracellularly = ammonia can only be broken down in liver
Ammonia broken down in liver to urea = urea accumulation in the blood
Urea in blood that travels to brain leads to hepatic coma
