Heather Chandler asks, “Based on this preprint study—”.
I have no idea if I've looked at this, so I’ll click it open just in case and I'll make
sure to include a link to the study that we're discussing in the show notes of this episode.
So, based on this preprint study called iron absorption from supplements is greater with
alternate day than with consecutive day dosing in iron deficient anemic women.
Heather has started taking supplemental iron every other day. She adds that the study suggests higher
absorption with every other day dosing because iron supplementation acutely upregulates hepcidin
for 24 hours. Can you explain the relationship between hepcidin and zinc
and would you expect every other day dosing might increase
zinc absorption also? How many minerals are impacted by hepcidin?
All right, I don't know if I can even answer this question, but let me take a look at this
study. So, according to this abstract, in iron depleted women without anemia, oral iron
supplements induce an increase in serum hepcidin that persist for 24 hours, decreasing iron
absorption from supplements given later on the same or next day. Consequently, iron absorption
from supplements is highest if iron is given on alternate days. Whether this dosing schedule is
also beneficial women with iron deficiency anemia given high dose iron supplements is uncertain.
The primary objective of this study was to assess whether in women with iron deficiency anemia
alternate day administration of 100 and 200 mg of iron increases— that's a very big dose of iron—
iron absorption compared to consecutive day iron administration. So, right away,
the language that they’re using is suspicious. So, I wanna see not whether the fractional absorption
of iron is increased, but whether the total amount of iron is any higher. So, I'll be looking
for that as I look further. So, if secondary objectives were to correlate iron absorption
with serum hepcidin and iron status parameters, we’ve performed a crossover iron absorption study
in women with iron deficiency anemia— there were 19 women— who received the doses that
they just mentioned of ferrous sulfate, which I wouldn't wanna take and blah, blah, blah. Okay.
Iron absorption on days 2 and 3 for consecutive dosing and day 5 for alternate dosing
and so on— day 5 with alternate dosing would be after there were 2 or 3 or 2 doses I guess—
was measured by measuring erythrocyte isotope incorporation. For both doses, serum hepcidin
was higher on day 3 than on day 2 or day 5 with no significant difference between days 2 and 5.
Similarly, for both doses, fractional iron absorption, right, which is the thing that
I'm not interested in, on days 2 and 5 was 40 to 50 percent higher than on day 3
while absorption on day 2 did not differ significantly from day 5. There was no significant
difference on the incidence of gastrointestinal side effects comparing the two iron doses.
Alternate day dosing of oral iron supplements in anemic women may be preferable
because it sharply increases fractional iron absorption. In order to provide the same total
amount of iron with alternate day dosing, twice the daily target should be given on alternate days
as total iron absorption from a single dose of 200 mg given on alternate days was approximately twice
that from 100 mg given on consecutive days. Even if iron deficiency anemia hepatic
hepcidin expression is wrongly suppressed by iron deficiency and erythropoietic drive, the intake of
oral iron supplements leads to an acute hepcidin increase for 24 hours. Okay. So, I get the logic.
I'm just very— It takes me a while especially when only looking at text to really assimilate stuff
like this. So, what they’re saying is hepcidin is a negative feedback loop for iron absorption.
So, if you have an increase in iron status or what this is showing is if you just have a bolus dose
of iron coming in, you're going to get a hepcidin response that is going to decrease iron absorption
and that short term boost in hepcidin lasts 24 hours. So, the logic is you have a big bolus dose
when the hepcidin is not elevated. That produces a negative feedback loop lasting 24 hours. So,
why dose yourself while that negative feedback loop is strong
when you could wait until the negative feedback loop is over and then dose yourself again?
I am exceedingly skeptical that this makes any sense in the long term
because, first of all this negative feedback loop isn't just controlled by bolus dosing of iron.
It's also controlled by iron status. And so, this is actually a very exquisite
system for basically ensuring that unless you have a malfunction in the system as do 8% of
the world's population with hemochromatosis genes, possibly higher than that depending on which ones
you count towards this— Actually, no. I believe it's 8% total for all the different alleles in it.
I'd have to double check that later. So, unless you have an impairment in the system or you have
iron intake that just no matter how much absorption you can extract of the system
is just not enough to prevent or reverse anemia, unless you're in those areas,
basically everyone should just have normal iron status no matter how much iron they’re eating.
That’s the logic of the hepcidin system. Now,
it may be the case that you get a 24-hour spike that goes away after 24 hours,
but let's say you start getting better iron absorption because you're practicing alternate
day higher dosing. They only measure this 2 doses out. So, what happens after the third,
fourth, and fifth dosing, you actually have better iron, better total iron absorption.
But then as iron status improves, more hepcidin kicks in anyway. And so, what are the chances
that this is going to be indefinitely extended out to the 10th, 20th, 40th, 50th dose of iron?
It seems that the maximal— I mean, unless this is actually tested out that length of dosing,
it seems that the maximal benefit of this would be that you might reverse anemia a little bit more
quickly. I question how frequently it actually is the primary concern to reverse anemia in like,
you know— to get a certain incremental increase in anemia reversal in 4 days versus 7, I just feel
like this is probably something that's going to kind of wash out in the long term. With that said,
I do wanna look at the data because I'm still confused whether there's a net benefit.
Individual fractional iron absorption from oral iron supplements taken on consecutive day 3
in alternate days day 5.
Okay. So, for a 100-mg iron dose, on the second dose, you've declined from— This is
individual people. They don't show the mean. So, it looks like you're declining from say 30
percent-ish to maybe 20 percent-ish on the second dose of consecutive day iron supplementation with
100 mg. With 200 mg, you're going from maybe 25 percent-ish to 10 percent-ish on consecutive day
fractional absorption. But if you alternate and you have 100 mg, you’re staying around maybe
30 percent-ish or even 25 percent-ish, for the median probably. About 25% instead of like 20%.
This is a real mess. So, one thing is that these responses between the different people
are exceedingly variable with 100-mg dose and they get less variable with the 200-mg dose
as everything basically gets pushed down towards a minimum of 8% absorption
and a median of around 15% absorption when taken every day. And when taken every other day, you
do have some people who retain— Like there is one person who retained 40% fractional absorption, but
the majority of the people are having their absorption pushed almost down as much as
with the consecutive day dosing because of the high dose.
So, the median here is probably somewhere around 15%. And it's not that much different for day 3.
So, their logic is that because consecutive dosing pushes down the fractional absorption, (fractional
absorption is what percentage of that one dose did you absorb), then you should take it every
other day, but double the dose. But doubling the dosing for most of the people up to 200 mg even on
every other day dosing substantially reduced fractional absorption down to the point where the
median fractional absorption has been pushed down to like 15%. So, to me, that strongly reinforces
what I was saying at the beginning that they're gonna be looking at fractional absorption and I'm
very skeptical that they actually had a sound conclusion about total absorption over time.
But then after looking at this data, it looks like there are probably some people who are going to
get a net quicker repletion of iron absorption on that protocol. But in the majority of the people
in that study, just having double the dose on every other day by the second of those doses,
fractional absorption was pushed down almost as much as it is with every day dosing. And so,
they only tested 2 doses. So, what happens after the third, fourth, fifth dose? I want see this
study before I waste my time with alternate day dosing. Bringing this back to a practical level,
is it easier for you to maintain a habit of every day dosing or is it easier for
you to maintain a habit of every other day dosing? Because I know for myself
by far and away, the easiest thing for me to do is to have a little turntable inside my cabinet
of everything I’m gonna take in the morning just take it all. The more complicated things get,
the more you need a list or you need an app that reminds you to take it every other day.
When I wake up in the morning half the time I am not going to remember whether I took it the day
before or not. So, I'm gonna have to keep track of that somehow. It's just so much more practical to
take something every day at the same time than it is to try to impose more complicated dosing
on it that I would want to be much more convinced that there is a real effect
before I was going to bother with that greater difficulty of sustaining the habit.