iron supplementation best every other day

 There was a recent study showing that alternate day oral iron supplementation in iron-deficient women was superior to daily supplementation (see iron def qod iron best LancetHeme2023 in dropbox, or  https://doi.org/10.1016/j.eclinm.2023.102286). Thanks to Ian Huntington for bringing this to my attention

 

Details:

-- 150 Swiss women aged 18-45 who participated in this double-blind, randomized, placebo-controlled trial, all having serum ferritin levels <30mcg/L (which equals 30 ng/mL), from 2021 to 2022

-- mean age 25, BMI 21

-- hemoglobin 13.3, MCV 90, hematocrit 41, serum iron 16 µmol, transferrin saturation 22%, ferritin 15.9 mcg/L, serum transferrin receptor 5 mg/L, body iron stores 2.7 mg/kg body weight, iron deficiency 36%

-- serum hepcidin level 0.6 nM [serum hepcidin levels inversely affect iron absorption]

-- participants were randomized to 100 mg of iron daily for 90 days, followed by placebo for another 90 days (the consecutive-day group) versus 100 mg of iron every other day for 180 days (alternate-day group): i.e. the same total iron dose but prescribed either daily or every other day

-- co-primary outcomes: serum ferritin and gastrointestinal side effects

-- secondary outcomes: serum ferritin deficiency (defined as serum ferritin <30mcg/L) and serum hepcidin levels

    -- all results were calculated in an intention-to-treat analysis

-- results were analyzed statistically using both mixed models to assess the effects of iron dosing and time on variables and longitudinal prevalence ratio (LPR) for GI adverse effects

 

Results:

-- medication adherence and reporting of side effects was >97% for each group

 

-- At the end of the six months treatment:

    -- mean serum ferritin was 43.8 mcg/L in the consecutive day group at day 93 versus 44.8 mcg/L in the alternate day group at day 186 (p=0.98), (ie, no difference after both groups received equal amounts of iron supplement)

    -- but at day 186 for both groups, there was quite a marked difference for both ferritin and hepcidin concentrations:

 

 

    -- iron deficiency prevalence after 3 months:

        -- consecutive day group: 5.5%

        -- alternate day group: 4.3%

            -- not statistically significant difference, p=0.74

    -- iron deficiency prevalence after 6 months:

        -- consecutive day group: 11.4%

        -- alternate day group: 3.0%

            -- statistically significant difference, p=0.049

 

-- Serum ferritin was higher in the consecutive day group at 46 and 93 days, but at 180 days the alternate day ferritin level was 44.8 versus consecutive day at 27.0 mcg/L, p<0.0001

 

-- serum hepcidin levels: higher in the consecutive day group on days 46 (p<0.0001) and 90 (p<0.001)

    -- comparing levels at day 90 for consecutive day group vs 180 for alternate day group (ie, both groups had received the same total iron intake): 3.0nM versus 1.9nM, p<0.0001

 

-- Fractional iron absorption (based on measured increase in serum ferritin and assumed obligatory iron losses over the full course of treatment):

    -- consecutive-day group: 4.1%

    -- alternate-day group: 5.5%

    -- 36.0% higher absorption in the alternate-day group, p <0.0001

 

-- no real difference in CRP, a-1-glycoprotein, intestinal fatty-acid binding protein, or fecal calprotectin levels between the groups

    -- the fecal calprotectin was measured as a marker of gut inflammation (to see if there were differences in the iron taken orally in terms of gut inflammation); the a-1-glycoprotein and CRP are other markers of inflammation

    -- the intestinal fatty-acid binding protein was measured to assess enterocyte damage

 

-- GI adverse effects:

    -- 91% more in the consecutive day group: LPR 1.91 (1.71-2.13); p<0.0001

        -- the adverse GI effects had the same difference between the groups (ie, better in the alternate day group) when assessing  them overall, mild effects, severe effects, and effects on the day taking the iron

 

Commentary:

-- iron deficiency anemia is quite common, especially in young women (about 20%, when using a ferritin cutoff of 13 mg/dL). A few studies have found numbers close to 30% in areas of low socioeconomic status in the US

-- serum hepcidin levels vary inversely with iron absorption (ie, a negative feedback loop with higher hepcidin levels leading to decreased iron absorption, presumably an evolutionary check on preventing iron overload??): after intake of iron supplements (>=60mg/d) serum hepcidin peaks at 8h, remains elevated at 24h, but decreases by 48h (hence the rationale for alternate day treatment)

-- all of the following were found to be statistically significantly better in the alternate day group at the 6 month mark: hemoglobin level, ferritin, iron deficiency anemia, hepcidin levels (and the related increase in the fractional iron absorption)

-- this study was done  by the same group that published two prior perspective open label randomized controlled trials, replicating the prior results of these smaller studies: see https://gmodestmedblogs.blogspot.com/2017/10/simplified-iron-supplementation-regimen.html:

    -- study 1: 40 young women with iron deficiency given 60mg iron daily for 14 days vs 60mg every other day for 28 days:

        --  fractional iron absorption was 16.3% in the former but 21.8% in the latter (cumulative iron absorption 131 vs 175mg); these results tracked inversely with serum hepcidin levels

    -- study 2: 20 young women with iron deficiency given 120 mg iron every morning vs 60mg every 12 hours, both for only 3 days

        -- cumulative iron absorption 11.8% vs 13.1% (not significant, but a really small study), with total iron absorbed 44 vs 49 mg, and results also tracking with serum hepcidin levels

-- the results of the current study were also found in studies in India and Turkey, though the current study had more women and longer treatment periods, and were methodologically better (eg double-blind RCT)

 

A few comments on serum ferritin as the marker for iron deficiency:

  -- the WHO defines iron deficiency as ferritin <34 pmol/L (which equals 15 ng/mL)

  -- but the issue here, I think, is the actual relationship between the ferritin levels we measure and the bone marrow iron stores, the accepted formal definition of iron status:

      -- ferritin is an acute phase reactant, and it is increased in infection, malignancy, or chronic inflammation (in contrast, soluble transferring receptor (sTfR) levels are not affected by inflammation or infection, though can be affected by hemolysis).

-- one concern is therefore the cutpoint for ferritin indicating iron deficiency and what the cutpoint is for subsequent iron repletion

    -- there are no great studies assessing iron deficiency comparing serum ferritin to bone marrow iron stores in healthy adults:

        -- one study from Australia assessed bone marrow aspirations in 76 adult patients (33 patients had hematological malignancies, 6 had biochemical iron deficiency, 2 solid tumors, and 35 had miscellaneous conditions including infection, autoimmune diseases, etc. (see iron def soluble transferrin receptor Path2007 in dropbox, or DOI: 10.1080/00313020701329732), finding:

            -- the most sensitive biochemical marker for the detection of absent bone marrow iron stories was sTfR, with a sensitivity of 100%.

            -- ferritin levels of at least 100 ng/mL had a sensitivity of 79% in detecting normal bone marrow iron stores, with a specificity of 83% for the detection of no bone marrow iron stores and 87.5% for reduced bone marrow iron stores

     -- another study from India, where iron deficiency is very prevalent (78% of lactating women, 75% of pregnant women, 70% of adolescent girls, 67% of preschool kids), with 39 participants (23 men), who had BM iron stores assessed for refractory anemia, pancytopenia, megaloblastic anemia, myelodysplastic syndromes, but excluded those with other malignancies, inflammatory conditions, and CKD, infections, finding:

            -- iron deficient bone marrows in 26 (15 men)

                -- serum ferritin of 100 ng/mL had a 100% sensitivity and 100% specificity for iron sufficiency (see https://pubmed.ncbi.nlm.nih.gov/28689489/ )

    -- a study of 42 individuals with heart failure (mean LVEF 38%) found 40% had no bone marrow iron, and their serum ferritin levels were between 44 to 169 ng/ml. They did find that transferrin saturation was a much better predictor than ferritin, with a 11.6-17.0% range in those who were iron deficient. sTfR was borderline significant in this study (https://pubmed.ncbi.nlm.nih.gov/29382661/ )

               -- so hard to generalize the above results to healthy individuals, given that the underlying medical conditions could possibly have increased ferritin levels a lot: ie, lack of bone marrow iron stores can occur with a ferritin of more than 100!!!!

    -- so what does this all  mean:

        -- a standard test we use for assessing iron deficiency is serum ferritin (though a low ferritin is relatively specific, a high ferritin is difficult to interpret)

            -- ie, people with ferritin even >100 could still have depleted stores of iron in their bone marrow, as above

            -- which also means that even in those with low ferritin and pretty clear iron deficiency, it is not clear what level of ferritin repletion is appropriate

        -- which means that we really need good studies to determine noninvasive, inexpensive markers with high correlates for iron deficiency in the general population

        -- which means that since we cannot do bone marrow evaluations on lots of people to assess their iron stores, perhaps there is a bone marrow MRI or some other evaluator that could be the gold standard for iron deficiency; and perhaps we can find another serum marker that correlates well with that in the population (both healthy and otherwise)???

  

Limitations:

-- this study was limited to women aged 18-45, so results may not be generalizable to men or older women

-- these women had quite mild iron deficiency, potentially limiting the generalizability to those with much more profound iron deficiency

-- the study compared disparate endpoints: the consecutive-day group had daily iron supplementation for 3 months, the alternate-day group had 6 months of medicine.

    -- what is the appropriate analysis: after the full dose of iron was taken, comparing the former at 3 months and latter at 6 months as in this study? But the former group with daily iron for 3 months had an additional 3 months to lose more blood and not get iron?

    -- the easiest way to avoid these issues would be to give the same total dose for 3 months (eg double dose the alternate-day group every other day and keep the consecutive day group at ½ that dose daily), then assess outcomes at 3 months, and best with additional assessment 3 months later, 1 year later…)

    -- or, perhaps giving a smaller dose (eg 30mg of iron) daily might not affect the hepcidin levels so much and work well

 

So,

-- our current understanding of the physiology of daily iron ingestion is that the increase in hepcidin leads to a decrease in iron absorption. this study confirmed that relationship and promotes the use of alternate day iron supplementation in those women who are iron deficient:

    -- but this conclusion assumes that our model is accurate, that there are no other factors (other than hepcidin) that affect serum iron levels (ie, our model may not be complete)

        -- ie, this strategy should be checked in a well-designed RCT

    -- one concern is that it may be more difficult in the real-world for patients to remember to take meds every other day vs daily (which would support studying if a lower dose of iron daily would work well)

--of course, for those women who are symptomatic from iron-deficiency or have very low hemoglobin levels (eg those not tolerating oral iron or have insufficient response, those who are symptomatic from iron deficiency, or perhaps those with a cutpoint hemoglobin less than 7 or so), there is the option of intravenous iron supplementation, which avoids the issue of hepcidin induced from oral iron intake

 

geoff

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