hello this is Eric again from Stanford University
and today I'll be discussing disorders of magnesium balance.
Historically magnesium in human physiology
has been largely ignored in most clinical circumstances
with the exception that everyone seems to love aggressively repeating it.
The reasons we tend to ignore magnesium disorders is twofold.
First, medical science has limited understanding of magnesium regulation
compared to other electrolytes. And second,
we have limited understanding the significance and frequency of
derangements in
magnesium balance. However in this video
I'll summarize the extent of what we do know. Before discussing pathology
let me start with an overview of normal homeostasis.
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
over,
which is in the blood. Of that 1 percent, 20 percent is bound to albumin,
10 percent is complexed to anions like
phosphate, and 70 percent is unbound,
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
is that serum magnesium levels correlate poorly
with total body magnesium content. Let's take a look at how magnesium homeostasis
is regulated.
As with all electrolytes, homeostasis begins the GI tract,
where orally consumed magnesium is absorbed, a process which appears to be
dependent upon
passive diffusion from the GI lumen, through the tight junctions between
epithelial cells and into the blood. Similar to calcium and phosphate homeostasis,
the bones act as a reservoir for huge amounts of magnesium.
Unlike calcium and phosphate however,
the magnesium in the bones is not in a tightly regulated equilibrium with the
blood,
and the bones do not happen nearly as important a role in
magnesium balance.
Magnesium is freely filtered through the glomeruli of the kidneys, where most is
reabsorbed again
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
between cells
down an electrochemical gradient which itself is partly generated by
reabsorption of sodium and chloride here. It is also dependent upon
a paracellular protein called called claudin 16, which is a constituent
of the tight junction between epithelial cells.
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.
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,
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.
As hypomagnesemia is rarely seen in isolation from other electrolyte abnormalities,
it's difficult to attribute specific symptoms to it.
Most symptoms are thought to
actually be caused by secondary abnormalities that are frequently
associated with, or even caused by hypomagnesemia.
For example, concurrent hypokalemia can lead to cardiac arrhythmias.
while concurrent hypercalcemia can lead to neuromuscular irritability
which can manifest as tremors, fasciculations, and tetany.
Whether hypomagnesemia in isolation can cause
these problems as well is actually not entirely clear.
In addition, there are some epidemiological studies that suggest a
link between chronic hypomagnesemia
and both hypertension and coronary artery disease, though a casual relationship
has not yet been clearly established.
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.
However, there are conditions in which hypomagnesemia
is associated with an increase risk of ventricular arrhythmias.
These include acute myocardial infarction, prolonged QT syndrome,
congestive heart failure, and digoxin toxicity.
lHypomagnesemia also increases the risk of a-fib following bypass surgery,
and may also increase the risk of a-fib in the general population.
Somewhat surprisingly, routine depletion of magnesium post-CABG
has not consistently been found to be beneficial.
There are a large number of causes of hypomagnesemia.
The first general mechanism is decreased GI uptake.
This obviously can be due to just poor dietary intake,
most commonly seen alcoholics. It is also observed in patients
on PPIs through an unknown mechanism,
or more appropriately through a not completely understood mechanism.
There's also a very rare disorder called primary familial
hypomagnesemia, the specific genetics at which are not yet fully worked-out
but which presents in infancy as hypocalcemia that's responsive to IV
magnesium therapy.
This secondary hypocalcemia is believed to be due to the effect of hypomagnesemia
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.
Magnesium is also present in proximal GI secretions,
which normally are largely reabsorbed later on in the GI tract.
However, in patients with chronic diarrhea and malabsorption,
and those with extensive inflammatory bowel disease. this reabsorption can be reduced
to the extent causing deficiency.
By far, the most varied general category of etiologies
is renal losses. Renal losses can be from medications,
most often loop and thiazide diuretics,
but also amphotericin B, aminoglycosides,
cisplatin, and calcineurin inhibitors are all classic causes of hypomagnesemia.
As mentioned earlier, hypercalcemia and hyperkalemia both inhibit magnesium reabsorption
in the renal tubules. Any process that causes a prominent osmotic diuresis
may disrupt the electrochemical gradient driving magnesium reabsorption
which can be seen in uncontrolled diabetes and during a post obstructive diuresis.
Alcohol is thought to cause transient tubular dysfunction,
which contributes to the nearly ubiquitous hypomagnesemia seen in
severe alcoholics.
Finally, there are a handful of rare familial renal magnesium wasting syndromes.
The most widely known is Gitelman syndrome - an autosomal recessive disease
caused by a defect in the thiazide-sensitive sodium chloride
co transporter in the distal tubule, which also results in
hypokalemia and a metabolic alkalosis from secondary hyperaldosteronism.
There are also a number of
very rare genetic defects affecting the claudin 16 protein
which lead to a syndrome of hypomagnesemia, hypercalciuria,
and nephrolithiasis.
Lastly, in the miscellaneous category is pancreatitis,
where magnesium and calcium salts can be involved in the saponification
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 my video on hypophosphatemia.
Moving on to the diagnostic evaluation of hypomagnesemia,
it's actually pretty easy as the etiology is usually evident from
the patient's history. However,
if it's not, one can calculate the fractional excretion of magnesium.
This is calculated as the product of the urine mag concentration
and the plasma creatinine divided by 0.7
times the plasma mag times the urine creatinine.
This is all then multiplied by 100 percent.
The 0.7 term here accounts for the fact that only about 70 percent of
circulating magnesium
is free and is able to be filtered across the glomerulus.
If the fractional excretion of mag is greater than 2 percent, it suggest
excessive renal losses. If it's less than 2 percent,
it suggests GI losses.
This calculation is rarely done in routine clinical practice.
When it comes to the treatment of hypomagnesemia, on one level,
it's simple - just give back magnesium.
On another level though, it can be a little tricky if one doesn't think hard
enough about the situation.
One reason for this is abrupt increases in serum mag, as
seen during IV administration, inhibit
mag reabsorption and lead to transient mag wasting,
which is obviously counterproductive.
Therefore, in the absence of symptoms, arrhythmias, or concurrent hypokalemia,
which greatly predisposes to arrhythmias, oral repletion is usually preferred.
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.
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
and may even be undesirable.
A practical question that quickly comes up and which is literally
never mentioned in the literature, is what should the goal magnesium level be
when undertaking repletion. In the US at least,
it's common practice to replete serum mag to high normal levels,
that is, greater than 2.0 milligrams per deciliter.
This practice is not based on strong evidence or guidelines, and
is probably not necessary for most patients.
Possible exceptions to this, that is, patients to still replete above 2
include those with acute MIs, those with active arrhythmias,
and those with long QT syndrome.
And please remember that one of the most common causes of hypermagnesemia is
iatrogenic excessive repletion
in patients who are either elderly and/or have renal impairment,
so therefore, please be careful with both the total dose
and the rate of repletion in these patients.
Let me down move onto hypermagnesemia.
I feel like because hypermagnesemia is often more abrupt and iatrogenic,
its easier to demonstrate that some findings are truly due to hypermagnesemia,
and not from other concurrent electrolyte disorders as with
hypomagnesemia.
These clinical manifestations fall into two main categories:
cardiovascular manifestations include bradycardia and conduction block,
which can progress to complete heart block and even asystole,
along with hypotension.
The other category is neuromuscular findings which include decreased reflexes,
muscle weakness, drowsiness progressing to coma,
and signs of parasympathetic blockade.
These signs include cutaneous flushing, dry mouth,
dilated pupils, and urinary retention.
The etiologies of hypermagnesemia are pretty minimal.
First is renal failure. The kidneys are the only known place in the body where
magnesium levels
are sort of regulated, and if they aren't working properly,
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
is simply excessive mag administration.
This can be in the form of massive PO intake from the laxative
magnesium citrate or from epsom salts.
It can be from excessive IV infusion, which can be seen during the treatment
of the life-threatening obstetric condition of eclampsia,
in which appropriate treatment almost always results in supernormal magnesium levels.
And finally, can be from magnesium containing enemas,
particularly when used in a patient with concurrent renal impairment.
And in fact, magnesium containing enemas are contraindicated
in that situation.
The only significant miscellaneous mechanism is tumor lysis syndrome,
in which a very large number of cancer cells either spontaneously
or in response to initiation of chemotherapy, suddenly die
and break apart releasing a large amount of intracellular magnesium
and in fact all their internal contents.
In general, the hypermagnesemia from this will be relatively minor issue
as compared to the hyperkalemia.
The diagnostic evaluation of hypermagnesemia is the easiest
of all electrolyte abnormalities as the etiology is
almost always evident from history and review renal function.
I personally have never encountered a patient with hypermagnesemia who
required any diagnostic evaluation beyond cursory
chart review.
The treatment of hypermagnesemia depends upon the patient's renal function.
If it's normal, the typical treatment is simply to stop the causative
magnesium containing medication.
If the patient has chronic kidney disease with a GFR on the order a 15 to 45,
or has non-anuric acute kidney injury,
a combination of normal saline and furosemide should be sufficient,
with solid attention given to maintaining appropriate volume status.
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
mag will be dialysis.
Finally, in a setting of acute, life-threatening hypermagnesemia,
IV calcium may temporarily antagonize activity
of the excessive mag.
It's possible that in another 10 or 20 years, we'll
know a lot more about this electrolyte but from a clinical standpoint,
that's all there is to say about it right now.
If you found this video interseting and useful,
you may want to check out my similar videos on calcium and phosphate
disorders.
or upcoming videos on sodium and potassium disorders