Iron Deficiency & Performance

Jeannie Callum, BA, MD, FRCPC, CTBS

Associate Professor,

Department of Laboratory

Medicine & Pathobiology

Does anemia matter?

Does frank iron deficiency matter?

Does a low ferritin 30-100 matter?

Does a high hemoglobin matter?

Does an even higher ferritin matter?

Outline

Iron science

Why are athletes iron deficient?

Consequences of iron deficiency on the:

Athletic performance

Cognitive function

Mood

How do you treat it?

Diet

Oral iron

Intravenous iron

Fe into the Enterocyte

Fe3+ H+

VC

Fe2+

Fe2+

FerrireductaseDMT1

Divalent Metal Transporter

• Fe2+

• Ca2+

• Cu2+

• Mg2+

• Cd2+

• Zn2+

• Other 2+ block by 40%

DMT1 SNPs

• Assoc with Fe def

• Assoc with RLS

DMT1 increases

with Fe def

Ferric

Heme into the enterocyte

Heme carrier protein 1

Increased expression with

hypoxia but not Fe def

Moves intracellularly

when Fe replete

Ferritin = protein cage ≠ iron

0 to 4500 Fe atoms

Problem: Acute phase reactant

The macrophage

Nurse cell

Hepcidin

An acute

phase reactant

Puts the body

in iron lockdown

Genetics of Hepcidin

HFE = hemochromatosis

TMPRSS6 = IRIDA

Hemochromatosis = hepcidin deficiency

Barton et al. Clin Genet 2006 Jan;69(1):48-57

40% 10%

Things I hate

20 to 400

Ferritin levels in “normals”

282/282 men = 700

All other men = 250

282/282 women = 300

All other women = 90

“Adequate iron” for women

“enough to get pregnant”

Each pregnancy requires 1000 mg of iron

Ferritin >50 ug/L (300 mg of iron)1 – 44%

Ferritin >70 ug/L (500 mg of iron)2 – 28%

Median ferritin in 1st trimester is 48 (IQR 43-51)3

Iron deficiency in pregnancy is associated with small

babies, premature delivery, anemia at delivery,

transfusion at delivery

1. Fernandez-Ballart J. Clin Drug Invest 2000; 19: S9-19.

2. Vandevijvere et al. J Acad Nutr Diet 2013; 113: 659-666.

3. Vandevijvere et al. J Acad Nutr Diet 2013; 113: 659-666.

How commom is iron deficiency anemia?Cusick SE, et al. Am J Clin Nutr 2008; 88: 1611-7.

The incidence of iron deficiency anemia has not

changed in the last 2 decades

1988-1994: Women 4.9% and Children 1.5%

1999-2002: Women 4.1% and Children 1.2%

1 in 20 women are anemic from iron deficiency

even before they start exercising

What about female athletes?

It is probably worse!

165 female collegiate rowers NY State

16 (10%) were anemic (Hgb

Gets worse over the season

20 elite rowing athletes and 10 professional soccer

players

At the end of season, 27% of all athletes had

absolute ID (

Elite men (half with HFE mutations)?

50 cyclists, 15 runners

HFE in athletes vs. couch potatoes?

Daily iron requirements

Men 0.8 mg/d

Women 1.4 mg/d; pregnancy 4-9 mg/d

4% of swallowed iron is absorbed in non-

deficient state

More than 1 mg though…

251 mg 1 mg

Hepcidin

Possible mechanisms why athletes don’t

have enough Fe

Diet – vegan/vegetarian, minimal beef/liver/clams

Poor absorption – HP infection, chronic exercise

induced gastritis, coffee/tea/dairy

GI bleeding – NSAIDS, gastritis

Hepcidin blockade – decreased absorption,

decreased recycling

Hemolysis – “March hemoglobinuria”

23

Hepcidin24

14 female

“Runners”

26.2 km

4-5 hr time

(7:04 min/km)

10/14 responders

4/14 no change

or 30%

Hepcidin & exercise

Peeling et al. PLoS One 2014 Mar 25;9(3):e93002

Effect can be blunted with post-exercise hypoxia

Inflammatory markers drive hepcidin up

26

Norway

21 Men

7 days

3 days x 20 km

with 45 kg pack

Inflammatory markers up from GI ischemia?

27

29 men in France performing an ironman

Cause – gut ischemia?

60-70% decrease in splanchnic blood flow at 70%

VO2-max

80% decrease at maximum exercise intensity

28

24 hours after a 330 mile run

45 randomized to famotidine vs. omeprazole

Scoped 24 hours after run

Exercise induced lesions lower with omeprazole

(2/23 vs. 7/21, p=0.049)

29

Humans – n=24

Long distance runners

Scoped

Zantac 150 mg bid x 2 weeks

Keep running

Repeat scopes

22/24 1+ GI lesion before (14 erosive gastritis

and 5 esophagitis)

11/14 and 4/5 healed with treatment

6/24 hemoccult+ before vs. 1/24 after

30

Most had no symptoms31

Consequences

Athletic

Cognitive

Mood

32

Impact on exercise capacityMcClung JP, et al. Am J Clin Nutr. 2009 Jul;90(1):124-31. Epub 2009 May 27.

Impaired exercise capacity

219 women undergoing basic combat training

randomized to 100 mg ferrous sulphate or placebo

(directly observed therapy)

Iron improved mood by ‘profile of mood state

questionnaire’ (p

Impact of iron deficiencyMcClung JP, et al. Am J Clin Nutr. 2009 Jul;90(1):124-31. Epub 2009 May 27.

Pass line

Black = placebo treated; gray = iron treated

6 min/km

19 minutes

3.2

km

US Air Force day 1 blood work

Severe – 100 for females, 115 for males

Run timesAll “iron deficient” supplemented

Men 135+ 130-134 115-129

Discharge/delayed

39 women, Hb>120, FTN

Outcomes

No change in

time trial

Fe lowered

Energy

Expenditure

5.1% lower

Fractional

Utilization

Of peak O2

Lower lactate

High hemoglobin pays off

Eero Mäntyranta

Finland

3 Gold

2 Silver

2 Bronze

236 g/L

//upload.wikimedia.org/wikipedia/commons/2/2a/EeroMantyranta.jpg

Non-anemic iron deficiency

Systematic review

17 studies in athletes

N=443 (n=80 men and n=363 women)

Age of 22.3 ±5.1 years

Ferritin by study

Improves hemoglobin in “non-anemic

athletes”!

Hedge’s g = 0.695

Improves VO2max44

Hedge’s g = 0.610

Female rowers

24 Fe depleted (

40 Rowers

RCT - Fe (vs. placebo) supplementation on Fe status

and performance in non-anemic female rowers

during training (all ferritins – median 25-28)

Rowers in the Fe group had slower lactate response

during the first half of the time trial and after 5 min

of recovery

Plus faster time trial, greater improvements in

energy expenditure and energetic efficiency

46

iv iron 300 mg – non-iron def!

14 Distance runners, Hb>120, ferritin>30

Fe carboxymaltose 100 mg x 3 (0,2,4 weeks)

Vs. placebo (saline)

47

48

49

Other measures50

Blood lactate Rating of perceived exertion

No improvement in time51

Impact of iron deficiency on cognitiveBruner AB et al. Lancet. 1996 Oct 12;348(9033):992-6.

Decreased cognitive function

81 non-anemic iron deficient girls at a Baltimore high

school

RCT – ferrous sulphate 325 mg bid or placebo x 8

weeks

Given 4 tests for cognitive function (attention and

memory)

Girls randomized to iron performed significantly better

than placebo treated girls (p

Cognitive speedBlanton et al. Br J Nutr. 2013 Mar 14;109(5):906-13

http://www.ajnr.org/content/21/8/1407/F1.large.jpg

Fatigue impact – PREFER trial (n=290)

Iron deficiency without anemia

Improvement

In fatigue

score

Treatment Options

Dietary iron

Oral iron

Salts – fumerate>sulfate>gluconate

Complex – FeraMax

Heme iron – Proferrin

No head to head trials!

Intravenous iron

Venofer 300 mg over 2 hours

FeraHeme 510 mg over 15 min

Ferinject 750 mg over 15 min

55

Dietary iron56

7 -8 th grade

3 months

Randomized

Chicken/Fish

Vs.

Beef

RCT – Vegetarian vs. Beef

Plus 3x per week exercise57

BASELINE WEEK 5 WEEK 12

Iron tablets

Tablet Iron Elemental Absorbed

Gluconate 300 35 1.4

Sulfate 300 60 2.4

Fumerate 300 100 4

Preg Vit 35 11 0.44

Materna 27 9 (4) 0.16

On empty stomach!

GI upset – 2-fold

Really important!

How to take oral iron:

Vitamin C

Empty stomach

No food

No other divalent metals

Better tolerated tablets?

More expensive

“Better absorption”

No evidence that more effective than oral iron salts

Dose

mg

Elemental

mg

Cost

Polysaccharide (Feramax) 150 150 $0.46

Heme iron (Proferrin) 398 11 $0.50

Systematic review: 17,793 pregnant women (48 RCTs)

Each 10 mg increase in dose per day decreased the risk of

anemia by 0.88 (0.84-0.92) (effect maxed out at 66 mg/d

of elemental)

WHO guidelines 1998 & 2007

60-120 mg elemental Fe/day

UK guidelines on IDA in pregnancy 2011

100-200 mg elemental Fe/day

British Society of Gastroenterology 2011

120 mg elemental Fe/day

What po dose for frank anemia?

Haider et al. BMJ 2013;346:f3443

Pavord et al. BCSH 2011

Goddard et al. Gut 2011;60:1309-16

Monitoring

How fast does the Hb rise?

Start to see effect in 2 weeks

Expect 15-20 g/L increase in 4 weeks

When to monitor?

Recheck hemoglobin at 2-4 weeks and then at 2-3

months

How long to treat?

Enough to recover Hb and replenish stores (~ 3-6

months) – target ferritin>100

Intravenous Iron

Indications Oral iron not tolerated

Oral iron absorption poor (other medications, infection, inflammation)

Oral iron not effective (e.g. ongoing bleeding)

Severe anemia (Hemoglobin < 90 g/L)

Different formulations available

Ferumoxytol (Feraheme 510mg)

Iron sucrose (Venofer 300mg)

iron sucrose ferumoxytol

Name Venofer Feraheme

Max single dose 300mg 510mg

Test dose No No

Infusion time 2 hours 15-60 min

Cost(ONT wholesale)

$39.56 (100mg)$145 / 300mg

$39.56 (100mg)$230 / 510mg

Life threatening ADE 0.6 per 106 (head to head studies with iron sucrose equivalent)

Munoz et al. Blood Transfus 2012;10:8-22; Chertow et al. Nephrol Dial Transpl 2006;21:378-82

Practical Considerations

Inform patient of side effects

Severe allergic reaction

Hypotension 1-2%

Other: headache, joint pains, GI upset

Monitoring

Reticulocytosis in 3-5 days

Expect 20-30 g/L in 4 weeks (if no ongoing bleeding)

Repeat Hb in 2 weeks

Ferritin not useful for 12 weeks (unless still really low)

Outline

Iron science

Iron physiology is REALLY complicated

Every patient is different – genetics are complicated

Why are athletes iron deficient?

Gut ischemia leading to erosions and high hepcidin plus for all the

reasons non-athletes get deficient

Consequences of iron deficiency on the:

Effects on athletic performance, cognitive function, perceived exertion

For sure 30

How do you treat it?

Diet – no evidence

Oral iron – coach them on how to take it

Intravenous iron – anemic and unresponsive, ferritin

Does anemia matter?

Does frank iron deficiency matter?

Does a low ferritin 30-100 matter?

Does a high hemoglobin matter?

Does an even higher ferritin matter?

Fix patients with iron deficiency!

Concentration Fitness

SadnessRestless legs

Low birth

weight infant

Transfusion