CHAPTER

 11  –  Iron  Metabolism   ♣ Non-­‐heme   iron:   Mainly   from  

  non-­‐meat   like   legumes   and  
 In   humans   70%   of   total   body   iron   is   vegetables,   approximately  
transported   in   the   ferrous   state   to   the   90%   of   the   dietary   irons   but  
heme  portion  of  hemoglobin   only  2  to  20%  is  absorbed.  
 5%  of  total  body  iron  is  bound  to  the    
myoglobin    Non-­‐heme   iron   enhancers   and  
 25%   of   total   body   iron   is   in   the   iron   inhibitors:  
storage   forms   Ferritin   and    
Hemosiderin   that   are   distributed   to   ♣ Enhancers:  
the   liver   and   bone   marrow   in   a) Ascorbates  
hepatocytes  and  macrophages   b) Citrates  
 Less   than   1%   is   transported   through   c) Organic  and  amino  acids  
the  plasma  in  the  ferric  state  bound  to    
transferrin   ♣ Inhibitors:  
 Mitochondrial   cytochrome   P-­‐450   a) Phytates  
(CYP   450)   or   cytochrome   oxidase   is   b) Polyphenols  
an  enzymatic  system  that  is  bound  to   c) Phosphates  
the   mitochondrial   membranes   which   d) Oxalates  
supports   oxidation   reduction   reaction   e) Calcium  
from  free  oxygen,  less  than  1%  of  the    
total   body   iron   can   be   found   in   this   Iron  absorption  and  excretion  
system    Duodenum  and  upper  jejunum  are  the  
 Concentration   of   storage   and   maximal  sites  of  iron  absorption  
transport   of   iron   is   controlled   by    For   transport   of   oxygen   in  
dietary   intake   and   iron   loss   through   Hemoglobin   iron   must   be   in   ferrous  
bleeding   form  
 Iron   deficiency   occurs   when   there   is    For   absorption   from   food   iron   must  
inadequate   iron   intake   or   excessive   be   in   the   heme   form   or   converted  
blood  loss  which  can  cause  anemia   from   ferric   non-­‐heme   iron   to   the  
 Iron   overload   results   from   increased   soluble  ferrous  form  by  a  duodenum-­‐
absorption   due   to   genetic   disposition   specific   cytochrome   b-­‐like   protein  
or   repeated   blood   transfusion   which   (DCYTB).  
can   cause   potential   fatal   heart   and    Uptake   of   heme   iron   occurs   on   heme  
liver  disease       carrier   protein   located   in   the   apical  
  membrane  of  the  duodenal  enterocyte  
Dietary  iron    Enzyme   heme   oxygenase   degrades  
 Iron   is   minimally   available.   In   an   heme  to  produce  ferrous  iron,  carbon  
average  American  diet  10  to  20  mg  of   dioxide  and  bilirubin-­‐IXa  
iron   is   present   but   only   1   to   2   mg   is     Ferrous   iron   is   transported   across  
absorbed  by  the  body   the  duodenal  epithelium  bound  to  the  
 Iron  is  absorbed  in  two  forms:   Apical   duodenal   metal   transporter   1  
♣ Heme   bound   iron:   Mainly   from   (DMT1)    
meat   and   is   absorbed   more    Ferrous   iron   is   then   carried   to   the  
efficiently.   5   to   35%   of   heme   basolateral   membrane   from   which   it  
iron   is   absorbed   as   hemin   is   exported   to   the   portal   circulation  
(iron  containing  porphyrin)   mediated  by  the  ferroportin.  
  Ferroportin   works   in   conjunction    Iron   circulates   in   RBC   in   the   ferrous  
with  a  copper  containing  iron  oxidase   form,   noncovalently   bound   to   the   Hb  
known  as  hephaestin.   molecule  
 Hephaestin   may   facilitate   iron    Iron   from   senescent   RBC   is   turned  
excretion   by   converting   ferrous   to   over  to  the  macrophages  and  reused  
ferric   iron.   The   ferric   iron   then   must    Ferrokinetics   involve   transferrin,  
be   bound   to   transferrin   to   be   transferrin   receptors,   and   ferritin.  
transported  in  the  circulation.     These   are   regulated   by   iron-­‐
 Some  irons  remains  in  the  enterocyte   responsive  protein  (IRP)  
as  ferritin  and  is  released  in  the  stool    Plasma  transferrin  is  produced  in  the  
 Hepcidin,   an   antimicrobial   peptide   hepatocytes.   Their   major   function   is  
produced  in  the  liver,  seems  to  act  as   the   transport   of   iron   form   the  
a  negative  regulator  of  intestinal  iron   enterocytes   of   duodenum   to  
absorption   transferrin  receptors  on  normoblasts    
 Hepcidin   binds   to   the   ferroportin    Plasma   transferrin   has   a   half   life   of   8  
receptor,   causing   degradation   of   days   and   migrates   to   β   fraction   in  
ferroportin   and   trapping   iron   in   the   electrophoresis  
intestinal  cells    Transferrin  molecules  can  exist  as:  
 High   levels   of   Hepcidin   can   result   to   a) Apotransferrin-­‐   no   iron   is  
transferrin   saturation   while   low   attached  
levels   of   Hepcidin   can   result   to   low   b) Monoferric   form-­‐   one   iron   is  
iron  saturation   attached  
 Iron   is   transported   across   the   c) Diferric   form-­‐   two   iron   is  
endosomal   membrane   by   DMT1   and   attached  
is   used   in   the   synthesis   of   iron-­‐  Transferrin  gene  is  located  in  the  long  
containing  protein.   arm  of  chromosome  3  
 Excess   iron   is   stored   as   ferritin   or    Transferrin   receptors   are  
hemosiderin   glycoprotein  dimmer  and  is  located  in  
 Humans   have   to   effective   means   to   all  cells  except  mature  RBCs  
excrete  iron.  Instead  we  regulate  iron    Control   of   transferrin   receptor  
by  controlling  absorption   biosynthesis   is   a   major   mechanism  
 Normal  iron  loss  through:   for  regulation  of  iron  metabolism  
a) Feces  is  about  1  mg  per  day    When   transferrin   is   congenitally  
b) Perspiration   and   skin   and   absent,   iron   is   absorbed   by   the  
dermal   appendages   exfoliation   intestine  and  accumulates  in  the  liver,  
has  minimal  loss   pancreas,   spleen   and   other   viscera;  
c) Lactation   and   menstruation   is   only   little   makes   its   way   to   the  
about  1  mg  per  day   marrow   and   a   severe   hypochromic  
  microcytic  anemia  results  
Iron  Cycle  and  transport      Cellular   uptake   of   iron   is   mediated  
 Iron   is   absorbed   from   the   GI   tract   and   largely   by   interaction   of   the  
transported   to   the   bone   marrow   transferrin   receptor   and   the  
where   it   is   inserted   to   the   transferrin  molecule.  
protoporphyrin   IX   to   make   heme.    Iron   enters   “chelatable”   soluble   pool  
Hemoglobin   synthesis   is   completed   in   in   the   cell,   where   it   is   used   for  
the  reticulocyte  stage   synthesis   of   essential   cellular  
constituents   or   for   disposition   as  
 ferritin,   a   non-­‐toxic   storage   form   of    High  sTfR  
iron.   ♣ Lack  in  iron  
 Iron-­‐responsive   proteins   (IRP)   binds   ♣ Ineffective  erythropoeisis  
Iron-­‐responsive  elements  (IRE)  when   ♣ Differentiate  IDA  from  anemia  of  
iron   supply   is   decreased   and   chronic  disease  (sTfR  index)  
dissociate   from   IREs   when   iron    Visual   qualitative   assessment   of  
supply  is  increased   tissue  iron  stores:  
  ♣ Bone  marrow  and  liver  biopsy  
Iron  storage   ♣ Prussian  blue  reaction  
 Iron   is   stored   in   an   accessible   form   as    Direct   assessment   of   functional   iron  
ferritin   or   as   partially   degraded   or   available   through   bone   marrow  
precipitated   form   of   ferritin   called   sideroblast  count  (nRBC  with  iron)  
hemosiderin    
 Apoferitin   is   the   protein   component  
of   ferritin   without   the   iron   and   is  
composed  of:  
a) L     (light)   subunits-­‐   found   in  
chromosome   19   in   the   liver,  
spleen  
b) H   (heavy)   subunits-­‐   found   in  
chromosome  11  in  the  heart  
 
Laboratory  assessment  
 Serum   iron   concentration   –   is   a  
measure   of   Fe3+   bound   to   serum  
transferrin   and   does   not   include   free  
serum  Hb  iron  
 Serum   unsaturated   iron-­‐binding  
capacity   (UIBC)   –   iron   binding   sites  
that  do  not  carry  iron  
 UIBC   is   measured   using   chromogen  
spectrophotometry    
 Total   iron   binding   capacity   (TIBC)-­‐  
Total  available  iron  binding  sites  
 TIBC   can   be   measured   indirectly   by  
chemical   means   and   directly   by  
immunoassay  
 Percent   transferrin   saturation   –  
percent  of  sites  available  for  carrying  
iron  
 Indicator  of  functional  iron  available  
♣ Serum   transferrin   receptor  
(sTfR)  index  
♣ RBC  zinc  protoporphyrin  
 Serum   transferrin   receptors   (sTfR)  
can  be  measured  by  immunoassay