hello this is Eric again from Stanford University
hello this is Eric again from Stanford University

and today I'll be discussing disorders of magnesium balance.
and today I'll be discussing disorders of magnesium balance.

Historically magnesium in human physiology
Historically magnesium in human physiology

has been largely ignored in most clinical circumstances
has been largely ignored in most clinical circumstances

with the exception that everyone seems to love aggressively repeating it.
with the exception that everyone seems to love aggressively repeating it.

The reasons we tend to ignore magnesium disorders is twofold.
The reasons we tend to ignore magnesium disorders is twofold.

First, medical science has limited understanding of magnesium regulation
First, medical science has limited understanding of magnesium regulation

compared to other electrolytes. And second,
compared to other electrolytes. And second,

we have limited understanding the significance and frequency of
we have limited understanding the significance and frequency of

derangements in
derangements in

magnesium balance. However in this video
magnesium balance. However in this video

I'll summarize the extent of what we do know. Before discussing pathology
I'll summarize the extent of what we do know. Before discussing pathology

let me start with an overview of normal homeostasis.
let me start with an overview of normal homeostasis.

Of the magnesium in the body about 50 percent is stored in the bones
Of the magnesium in the body about 50 percent is stored in the bones

and about 50 percent is in the intracellular space. There's actually about 1 percent left
and about 50 percent is in the intracellular space. There's actually about 1 percent left

over,
over,

which is in the blood. Of that 1 percent, 20 percent is bound to albumin,
which is in the blood. Of that 1 percent, 20 percent is bound to albumin,

10 percent is complexed to anions like
10 percent is complexed to anions like

phosphate, and 70 percent is unbound,
phosphate, and 70 percent is unbound,

which is the biologically active form. The consequence of the fact that
which is the biologically active form. The consequence of the fact that

only a tiny fraction the body's magnesium is present in the blood
only a tiny fraction the body's magnesium is present in the blood

is that serum magnesium levels correlate poorly
is that serum magnesium levels correlate poorly

with total body magnesium content. Let's take a look at how magnesium homeostasis
with total body magnesium content. Let's take a look at how magnesium homeostasis

is regulated.
is regulated.

As with all electrolytes, homeostasis begins the GI tract,
As with all electrolytes, homeostasis begins the GI tract,

where orally consumed magnesium is absorbed, a process which appears to be
where orally consumed magnesium is absorbed, a process which appears to be

dependent upon
dependent upon

passive diffusion from the GI lumen, through the tight junctions between
passive diffusion from the GI lumen, through the tight junctions between

epithelial cells and into the blood. Similar to calcium and phosphate homeostasis,
epithelial cells and into the blood. Similar to calcium and phosphate homeostasis,

the bones act as a reservoir for huge amounts of magnesium.
the bones act as a reservoir for huge amounts of magnesium.

Unlike calcium and phosphate however,
Unlike calcium and phosphate however,

the magnesium in the bones is not in a tightly regulated equilibrium with the
the magnesium in the bones is not in a tightly regulated equilibrium with the

blood,
blood,

and the bones do not happen nearly as important a role in
and the bones do not happen nearly as important a role in

magnesium balance.
magnesium balance.

Magnesium is freely filtered through the glomeruli of the kidneys, where most is
Magnesium is freely filtered through the glomeruli of the kidneys, where most is

reabsorbed again
reabsorbed again

in the thick ascending limb of the loop of Henle. As with the gut,
in the thick ascending limb of the loop of Henle. As with the gut,

most magnesium transport in the kidneys is due to passive diffusion
most magnesium transport in the kidneys is due to passive diffusion

between cells
between cells

down an electrochemical gradient which itself is partly generated by
down an electrochemical gradient which itself is partly generated by

reabsorption of sodium and chloride here. It is also dependent upon
reabsorption of sodium and chloride here. It is also dependent upon

a paracellular protein called called claudin 16, which is a constituent
a paracellular protein called called claudin 16, which is a constituent

of the tight junction between epithelial cells.
of the tight junction between epithelial cells.

Overall, there are no known hormones or enzymes that directly regulate magnesium balance.
Overall, there are no known hormones or enzymes that directly regulate magnesium balance.

That's not to say there aren't any. Just that we don't understand them yet.
That's not to say there aren't any. Just that we don't understand them yet.

However, what regulation we do know about occurs mostly in the renal tubule where a number of metabolic derangements
However, what regulation we do know about occurs mostly in the renal tubule where a number of metabolic derangements

affect magnesium reabsorption. Derrangements which prevent reabsorption,
affect magnesium reabsorption. Derrangements which prevent reabsorption,

and thus lead to hypomagnesemia include low potassium, high calcium, high magneseium (obviously), and a low serum pH.
and thus lead to hypomagnesemia include low potassium, high calcium, high magneseium (obviously), and a low serum pH.

This is a good time to transition to hypomagnesemia.
This is a good time to transition to hypomagnesemia.

As hypomagnesemia is rarely seen in isolation from other electrolyte abnormalities,
As hypomagnesemia is rarely seen in isolation from other electrolyte abnormalities,

it's difficult to attribute specific symptoms to it.
it's difficult to attribute specific symptoms to it.

Most symptoms are thought to
Most symptoms are thought to

actually be caused by secondary abnormalities that are frequently
actually be caused by secondary abnormalities that are frequently

associated with, or even caused by hypomagnesemia.
associated with, or even caused by hypomagnesemia.

For example, concurrent hypokalemia can lead to cardiac arrhythmias.
For example, concurrent hypokalemia can lead to cardiac arrhythmias.

while concurrent hypercalcemia can lead to neuromuscular irritability
while concurrent hypercalcemia can lead to neuromuscular irritability

which can manifest as tremors, fasciculations, and tetany.
which can manifest as tremors, fasciculations, and tetany.

Whether hypomagnesemia in isolation can cause
Whether hypomagnesemia in isolation can cause

these problems as well is actually not entirely clear.
these problems as well is actually not entirely clear.

In addition, there are some epidemiological studies that suggest a
In addition, there are some epidemiological studies that suggest a

link between chronic hypomagnesemia
link between chronic hypomagnesemia

and both hypertension and coronary artery disease, though a casual relationship
and both hypertension and coronary artery disease, though a casual relationship

has not yet been clearly established.
has not yet been clearly established.

In a similar manner, despite occasional claims to the contrary there are probably no specific
In a similar manner, despite occasional claims to the contrary there are probably no specific

abnormalities of the waveforms on the EKG that are specifically suggestive of hypomagnesemia.
abnormalities of the waveforms on the EKG that are specifically suggestive of hypomagnesemia.

However, there are conditions in which hypomagnesemia
However, there are conditions in which hypomagnesemia

is associated with an increase risk of ventricular arrhythmias.
is associated with an increase risk of ventricular arrhythmias.

These include acute myocardial infarction, prolonged QT syndrome,
These include acute myocardial infarction, prolonged QT syndrome,

congestive heart failure, and digoxin toxicity.
congestive heart failure, and digoxin toxicity.

lHypomagnesemia also increases the risk of a-fib following bypass surgery,
lHypomagnesemia also increases the risk of a-fib following bypass surgery,

and may also increase the risk of a-fib in the general population.
and may also increase the risk of a-fib in the general population.

Somewhat surprisingly, routine depletion of magnesium post-CABG
Somewhat surprisingly, routine depletion of magnesium post-CABG

has not consistently been found to be beneficial.
has not consistently been found to be beneficial.

There are a large number of causes of hypomagnesemia.
There are a large number of causes of hypomagnesemia.

The first general mechanism is decreased GI uptake.
The first general mechanism is decreased GI uptake.

This obviously can be due to just poor dietary intake,
This obviously can be due to just poor dietary intake,

most commonly seen alcoholics. It is also observed in patients
most commonly seen alcoholics. It is also observed in patients

on PPIs through an unknown mechanism,
on PPIs through an unknown mechanism,

or more appropriately through a not completely understood mechanism.
or more appropriately through a not completely understood mechanism.

There's also a very rare disorder called primary familial
There's also a very rare disorder called primary familial

hypomagnesemia, the specific genetics at which are not yet fully worked-out
hypomagnesemia, the specific genetics at which are not yet fully worked-out

but which presents in infancy as hypocalcemia that's responsive to IV
but which presents in infancy as hypocalcemia that's responsive to IV

magnesium therapy.
magnesium therapy.

This secondary hypocalcemia is believed to be due to the effect of hypomagnesemia
This secondary hypocalcemia is believed to be due to the effect of hypomagnesemia

lowering PTH secretion and increasing PTH resistance.
lowering PTH secretion and increasing PTH resistance.

This effect is explained in a little more detail in my video on normal calcium and phosphate physiology.
This effect is explained in a little more detail in my video on normal calcium and phosphate physiology.

Magnesium is also present in proximal GI secretions,
Magnesium is also present in proximal GI secretions,

which normally are largely reabsorbed later on in the GI tract.
which normally are largely reabsorbed later on in the GI tract.

However, in patients with chronic diarrhea and malabsorption,
However, in patients with chronic diarrhea and malabsorption,

and those with extensive inflammatory bowel disease. this reabsorption can be reduced
and those with extensive inflammatory bowel disease. this reabsorption can be reduced

to the extent causing deficiency.
to the extent causing deficiency.

By far, the most varied general category of etiologies
By far, the most varied general category of etiologies

is renal losses. Renal losses can be from medications,
is renal losses. Renal losses can be from medications,

most often loop and thiazide diuretics,
most often loop and thiazide diuretics,

but also amphotericin B, aminoglycosides,
but also amphotericin B, aminoglycosides,

cisplatin, and calcineurin inhibitors are all classic causes of hypomagnesemia.
cisplatin, and calcineurin inhibitors are all classic causes of hypomagnesemia.

As mentioned earlier, hypercalcemia and hyperkalemia both inhibit magnesium reabsorption
As mentioned earlier, hypercalcemia and hyperkalemia both inhibit magnesium reabsorption

in the renal tubules. Any process that causes a prominent osmotic diuresis
in the renal tubules. Any process that causes a prominent osmotic diuresis

may disrupt the electrochemical gradient driving magnesium reabsorption
may disrupt the electrochemical gradient driving magnesium reabsorption

which can be seen in uncontrolled diabetes and during a post obstructive diuresis.
which can be seen in uncontrolled diabetes and during a post obstructive diuresis.

Alcohol is thought to cause transient tubular dysfunction,
Alcohol is thought to cause transient tubular dysfunction,

which contributes to the nearly ubiquitous hypomagnesemia seen in
which contributes to the nearly ubiquitous hypomagnesemia seen in

severe alcoholics.
severe alcoholics.

Finally, there are a handful of rare familial renal magnesium wasting syndromes.
Finally, there are a handful of rare familial renal magnesium wasting syndromes.

The most widely known is Gitelman syndrome - an autosomal recessive disease
The most widely known is Gitelman syndrome - an autosomal recessive disease

caused by a defect in the thiazide-sensitive sodium chloride
caused by a defect in the thiazide-sensitive sodium chloride

co transporter in the distal tubule, which also results in
co transporter in the distal tubule, which also results in

hypokalemia and a metabolic alkalosis from secondary hyperaldosteronism.
hypokalemia and a metabolic alkalosis from secondary hyperaldosteronism.

There are also a number of
There are also a number of

very rare genetic defects affecting the claudin 16 protein
very rare genetic defects affecting the claudin 16 protein

which lead to a syndrome of hypomagnesemia, hypercalciuria,
which lead to a syndrome of hypomagnesemia, hypercalciuria,

and nephrolithiasis.
and nephrolithiasis.

Lastly, in the miscellaneous category is pancreatitis,
Lastly, in the miscellaneous category is pancreatitis,

where magnesium and calcium salts can be involved in the saponification
where magnesium and calcium salts can be involved in the saponification

of retroperitoneal fat. And magnesium can be quickly drawn up from the serum
of retroperitoneal fat. And magnesium can be quickly drawn up from the serum

in the hungry bone syndrome, described in a little more detail
in the hungry bone syndrome, described in a little more detail

in my video on hypophosphatemia.
in my video on hypophosphatemia.

Moving on to the diagnostic evaluation of hypomagnesemia,
Moving on to the diagnostic evaluation of hypomagnesemia,

it's actually pretty easy as the etiology is usually evident from
it's actually pretty easy as the etiology is usually evident from

the patient's history. However,
the patient's history. However,

if it's not, one can calculate the fractional excretion of magnesium.
if it's not, one can calculate the fractional excretion of magnesium.

This is calculated as the product of the urine mag concentration
This is calculated as the product of the urine mag concentration

and the plasma creatinine divided by 0.7
and the plasma creatinine divided by 0.7

times the plasma mag times the urine creatinine.
times the plasma mag times the urine creatinine.

This is all then multiplied by 100 percent.
This is all then multiplied by 100 percent.

The 0.7 term here accounts for the fact that only about 70 percent of
The 0.7 term here accounts for the fact that only about 70 percent of

circulating magnesium
circulating magnesium

is free and is able to be filtered across the glomerulus.
is free and is able to be filtered across the glomerulus.

If the fractional excretion of mag is greater than 2 percent, it suggest
If the fractional excretion of mag is greater than 2 percent, it suggest

excessive renal losses. If it's less than 2 percent,
excessive renal losses. If it's less than 2 percent,

it suggests GI losses.
it suggests GI losses.

This calculation is rarely done in routine clinical practice.
This calculation is rarely done in routine clinical practice.

When it comes to the treatment of hypomagnesemia, on one level,
When it comes to the treatment of hypomagnesemia, on one level,

it's simple - just give back magnesium.
it's simple - just give back magnesium.

On another level though, it can be a little tricky if one doesn't think hard
On another level though, it can be a little tricky if one doesn't think hard

enough about the situation.
enough about the situation.

One reason for this is abrupt increases in serum mag, as
One reason for this is abrupt increases in serum mag, as

seen during IV administration, inhibit
seen during IV administration, inhibit

mag reabsorption and lead to transient mag wasting,
mag reabsorption and lead to transient mag wasting,

which is obviously counterproductive.
which is obviously counterproductive.

Therefore, in the absence of symptoms, arrhythmias, or concurrent hypokalemia,
Therefore, in the absence of symptoms, arrhythmias, or concurrent hypokalemia,

which greatly predisposes to arrhythmias, oral repletion is usually preferred.
which greatly predisposes to arrhythmias, oral repletion is usually preferred.

On the other hand, if any of those are present
On the other hand, if any of those are present

IV mag can be given, usually 1-2 grams of magnesium sulfate at a time.
IV mag can be given, usually 1-2 grams of magnesium sulfate at a time.

Although it's a common practice to give IV mag relatively quickly,
Although it's a common practice to give IV mag relatively quickly,

that is, over less than 15 minutes per gram, this speed is usually not necessary
that is, over less than 15 minutes per gram, this speed is usually not necessary

and may even be undesirable.
and may even be undesirable.

A practical question that quickly comes up and which is literally
A practical question that quickly comes up and which is literally

never mentioned in the literature, is what should the goal magnesium level be
never mentioned in the literature, is what should the goal magnesium level be

when undertaking repletion. In the US at least,
when undertaking repletion. In the US at least,

it's common practice to replete serum mag to high normal levels,
it's common practice to replete serum mag to high normal levels,

that is, greater than 2.0 milligrams per deciliter.
that is, greater than 2.0 milligrams per deciliter.

This practice is not based on strong evidence or guidelines, and
This practice is not based on strong evidence or guidelines, and

is probably not necessary for most patients.
is probably not necessary for most patients.

Possible exceptions to this, that is, patients to still replete above 2
Possible exceptions to this, that is, patients to still replete above 2

include those with acute MIs, those with active arrhythmias,
include those with acute MIs, those with active arrhythmias,

and those with long QT syndrome.
and those with long QT syndrome.

And please remember that one of the most common causes of hypermagnesemia is
And please remember that one of the most common causes of hypermagnesemia is

iatrogenic excessive repletion
iatrogenic excessive repletion

in patients who are either elderly and/or have renal impairment,
in patients who are either elderly and/or have renal impairment,

so therefore, please be careful with both the total dose
so therefore, please be careful with both the total dose

and the rate of repletion in these patients.
and the rate of repletion in these patients.

Let me down move onto hypermagnesemia.
Let me down move onto hypermagnesemia.

I feel like because hypermagnesemia is often more abrupt and iatrogenic,
I feel like because hypermagnesemia is often more abrupt and iatrogenic,

its easier to demonstrate that some findings are truly due to hypermagnesemia,
its easier to demonstrate that some findings are truly due to hypermagnesemia,

and not from other concurrent electrolyte disorders as with
and not from other concurrent electrolyte disorders as with

hypomagnesemia.
hypomagnesemia.

These clinical manifestations fall into two main categories:
These clinical manifestations fall into two main categories:

cardiovascular manifestations include bradycardia and conduction block,
cardiovascular manifestations include bradycardia and conduction block,

which can progress to complete heart block and even asystole,
which can progress to complete heart block and even asystole,

along with hypotension.
along with hypotension.

The other category is neuromuscular findings which include decreased reflexes,
The other category is neuromuscular findings which include decreased reflexes,

muscle weakness, drowsiness progressing to coma,
muscle weakness, drowsiness progressing to coma,

and signs of parasympathetic blockade.
and signs of parasympathetic blockade.

These signs include cutaneous flushing, dry mouth,
These signs include cutaneous flushing, dry mouth,

dilated pupils, and urinary retention.
dilated pupils, and urinary retention.

The etiologies of hypermagnesemia are pretty minimal.
The etiologies of hypermagnesemia are pretty minimal.

First is renal failure. The kidneys are the only known place in the body where
First is renal failure. The kidneys are the only known place in the body where

magnesium levels
magnesium levels

are sort of regulated, and if they aren't working properly,
are sort of regulated, and if they aren't working properly,

there is no way for the body to get rid of excessive magnesium
there is no way for the body to get rid of excessive magnesium

that it may have absorbed from the gut. The next mechanism of hypermagnesemia
that it may have absorbed from the gut. The next mechanism of hypermagnesemia

is simply excessive mag administration.
is simply excessive mag administration.

This can be in the form of massive PO intake from the laxative
This can be in the form of massive PO intake from the laxative

magnesium citrate or from epsom salts.
magnesium citrate or from epsom salts.

It can be from excessive IV infusion, which can be seen during the treatment
It can be from excessive IV infusion, which can be seen during the treatment

of the life-threatening obstetric condition of eclampsia,
of the life-threatening obstetric condition of eclampsia,

in which appropriate treatment almost always results in supernormal magnesium levels.
in which appropriate treatment almost always results in supernormal magnesium levels.

And finally, can be from magnesium containing enemas,
And finally, can be from magnesium containing enemas,

particularly when used in a patient with concurrent renal impairment.
particularly when used in a patient with concurrent renal impairment.

And in fact, magnesium containing enemas are contraindicated
And in fact, magnesium containing enemas are contraindicated

in that situation.
in that situation.

The only significant miscellaneous mechanism is tumor lysis syndrome,
The only significant miscellaneous mechanism is tumor lysis syndrome,

in which a very large number of cancer cells either spontaneously
in which a very large number of cancer cells either spontaneously

or in response to initiation of chemotherapy, suddenly die
or in response to initiation of chemotherapy, suddenly die

and break apart releasing a large amount of intracellular magnesium
and break apart releasing a large amount of intracellular magnesium

and in fact all their internal contents.
and in fact all their internal contents.

In general, the hypermagnesemia from this will be relatively minor issue
In general, the hypermagnesemia from this will be relatively minor issue

as compared to the hyperkalemia.
as compared to the hyperkalemia.

The diagnostic evaluation of hypermagnesemia is the easiest
The diagnostic evaluation of hypermagnesemia is the easiest

of all electrolyte abnormalities as the etiology is
of all electrolyte abnormalities as the etiology is

almost always evident from history and review renal function.
almost always evident from history and review renal function.

I personally have never encountered a patient with hypermagnesemia who
I personally have never encountered a patient with hypermagnesemia who

required any diagnostic evaluation beyond cursory
required any diagnostic evaluation beyond cursory

chart review.
chart review.

The treatment of hypermagnesemia depends upon the patient's renal function.
The treatment of hypermagnesemia depends upon the patient's renal function.

If it's normal, the typical treatment is simply to stop the causative
If it's normal, the typical treatment is simply to stop the causative

magnesium containing medication.
magnesium containing medication.

If the patient has chronic kidney disease with a GFR on the order a 15 to 45,
If the patient has chronic kidney disease with a GFR on the order a 15 to 45,

or has non-anuric acute kidney injury,
or has non-anuric acute kidney injury,

a combination of normal saline and furosemide should be sufficient,
a combination of normal saline and furosemide should be sufficient,

with solid attention given to maintaining appropriate volume status.
with solid attention given to maintaining appropriate volume status.

If the patient has chronic kidney disease with a GFR under 15
If the patient has chronic kidney disease with a GFR under 15

or has anuric kidney injury, the only way to get rid of the excess
or has anuric kidney injury, the only way to get rid of the excess

mag will be dialysis.
mag will be dialysis.

Finally, in a setting of acute, life-threatening hypermagnesemia,
Finally, in a setting of acute, life-threatening hypermagnesemia,

IV calcium may temporarily antagonize activity
IV calcium may temporarily antagonize activity

of the excessive mag.
of the excessive mag.

It's possible that in another 10 or 20 years, we'll
It's possible that in another 10 or 20 years, we'll

know a lot more about this electrolyte but from a clinical standpoint,
know a lot more about this electrolyte but from a clinical standpoint,

that's all there is to say about it right now.
that's all there is to say about it right now.

If you found this video interseting and useful,
If you found this video interseting and useful,

you may want to check out my similar videos on calcium and phosphate
you may want to check out my similar videos on calcium and phosphate

disorders.
disorders.

or upcoming videos on sodium and potassium disorders
or upcoming videos on sodium and potassium disorders