IM-A: HEMATOLOGY

1.4 IRON DEFICIENCY ANEM IAS & OTHER HYPOPROLIFERATIVE DISORDERS

Date: August 4, 2015
FEU-NRMF School of Medicine
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IRON  DEFICIENCY  ANEMIA   FERRITIN   HEMOSIDERIN  
è Considered  Microcytic,  Hypochromic  type  of  anemia   Water  soluble   Water  insoluble  
è There  is  a  reduction  in  Erythropoietin  response.   Found  in  the  blood   Found   in   tissues  
è MOST  COMMON  CAUSE  OF  ANEMIA  WORLDWIDE  and  the   (macrophages)  
MOST   IMPORTANT   CAUSE   OF   MICROCYTIC   Correlates   roughly   with    
HYPOCHROMIC  ANEMIA   total   body   iron   stores   (LOW  
è 50%  of  cases   SERUM   FERRITIN   indicates  
è In  the  PHILIPPINES:   LOW  IRON  STORAGE)  
o It   is   a   public   health   concern   among   6   months   to   1   Adult  men:  800-­‐1000mg    
year  old  and  Pregnant,  Lactating  women.   Adult  women:  Few  hundred  
o Prevalence   of   IDA   in   the   PH   (2003),   Pregnant   mg  
Women   (43.9%),   Lactating   Women   (42.2%)   and   Used  in  the  diagnosis  of  IDA    
Infants  (66.2%)    
PATHOPHYSIOLOGY  OF  MICROCYTIC  HYPOCHROMIC  ANEMIA   MYOGLOBIN  
è Found  in  the  skeletal  and  cardiac  muscle  tissues  
è Immediate  iron  stores  
è In   O2   deprivation,   myoglobin   IRON   is   stimulated   so   the  
supply   of   Iron   in   the   tissues   (Cardiac,   Skeletal)   won’t   be  
depleted  
HEME  ENZYMES  
è Enzymes   that   are   responsible   for   metabolism,   contains  
iron.  (e.g.  CYTOCHROMES)  
TRANSPORT  IRON  
è Smallest  but  most  active  iron  compartment.  
è Iron  normally  turns  over  at  least  10x  each  day.  
è Common   pathway   for   interchange   of   iron   between  
compartments.  
è Bound  to  transferrin  (5%  of  total  binding  iron)  
  è Trans  
è There  are  different  elements  in  the  hemoglobin  synthesis:   BODY  IRON  DISTRIBUTION  and  TRANSPORT  
HEME  and  GLOBIN  in  order  to  form  the  hemoglobin   è Mediated  by  4  PROTEINS:  
è If   you   have   a   problem   with   IRON   SUPPLEMENTATION;  
TRANSFERRIN   Transport  protein  for  iron  
there   will   be   a   decrease   in   production   of   Hemoglobin,  
TRANSFERRIN   Expressed  mostly  by  the  red  cell  and  the  
Chronic  Inflammation  and  malignancy.  
RECEPTOR  1   liver  
è Problems   in   the   PROTORPHYRIN   will   give   rise   to  
FERRITIN   Major  storage  form  of  IRON  
SIDEROBLASTIC  TYPE  OF  ANEMIA  
HEPCIDIN   Regulator  of  Iron  metabolism  
è GLOBIN  problems  will  incur  THALASSAEMIA  (alpha  or  beta)  
   
THE  IRON  CYCLE  
METABOLISM  OF  IRON  
TOTAL  BODY    
COMPARTMENT   MALE  (g)   FEMALE  (g)  
IRON  (%)    
HEMOGLOBIN  IRON   2.4   1.7   65  
 
STORAGE  IRON  (Ferritin,   1.0  (0.3-­‐1.5)   0.3  (0-­‐1.0)   30  
Hemosiderin)    
MYOGLOBIN  IRON   0.15   0.12   3.5    
HEME  ENZYMES   0.02   0.015   0.5  
TRANSPORT  IRON   0.004   0.003   0.1  
 
HEME  IRON    
è The   iron   in   hemoglobin   makes   up   the   great   bulk   of   heme    
iron.  Each  gram  of  HEMOGLOBIN  contains  3.4  mg  of  IRON.    
(One  ml  of  PACKED  RED  CELLS  =  1  mg  of  IRON)    
STORAGE  IRON:    
   
   

KIM  VILLANUEVA,  PTRP  (3A)   1  

 
   è The   Iron   that   is   in   the   cytoplasm   of   the   cell   will   cause  
  acidification   because   of   the   hydrogen   available   in   the  
  cytoplasm.  
è The   amount   of   Iron   absorbed   by   a   normal   adult   male   need    
only  the  small  amount  that  is  excreted.  (approx  1mg  /day)    
è A  higher  iron  requirement  exists  during  growth  periods  or   FACTORS   FAVOURING   IRON   FACTORS   REDUCING   IRON  
ABSORPTION   ABSORPTION  
when  there  is  blood  loss.  
Heme  iron   Inorganic  iron  
è In  women,  Iron  absorbed  must  be  sufficient  to  replace  the   Ferrous  form   Ferric  form  
loss   during   menstration   or   diversion   to   the   fetus   during   Acids  (HCl,  Vitamin  C)   Alkalis  –  antacids,  pancreatic  seretions  
pregnancy.   Solubilizing   agents   (sugars,   amino   Precipitating   agents   –   phylates,  
è Daily  absorbption:   acids)   phosphates,  tea  
o 4  mg   Reduced   serum   hepcidin   (e.g.   IRON   Increased  serum  hepcidin  
o Transferrin:  4mg   DEFICIENCY)  
Ineffective  erythropoiesis   Decreased  erythropoiesis  
o Bone  marrow:  150mg  is  present  
Pregnancy   Inflammation  
o Macrophage:  0.5-­‐1.5g     Hereditary  hemochromatosis    
o Red  Cell:  1.7-­‐2.4  g   Increased   expression   of   DMT-­‐1   in   Decreased   expressionof   DMT-­‐1   in  
o Liver:  650mg   duodenal  enterocytes   duodenal  enterocytes  
è In  cases  of  IRON  overload;  most  of  the  iron  is  taken  up  by     Gastrectomy,   achlorydia:   mucosal  
the  macrophage.   absorption  
è If  the  capacity  of  the  macrophage  is  exceeded,  it  will  then    
be  transferred  to  the  parenchymal  cells  of  the  liver.   è Iron  is  absorbed  best  without  food  so  take  it  with  an  empty  
è One   of   the   consequences   of   IRON   OVERLOAD   is   LIVER   stomach  
CIRRHOSIS.   è Pts   with   GI   diseases,   take   the   PPI   in   the   morning   and   the  
IRON  ABSORPTION  (REVIEW  TO  NG  BIOCHEM)   iron  supplement  after  lunch.  
  è Iron  is  absorbed   in   the   duodenal   mucosa.   If   patients   have  
small  bowel  surgery,  IV  supplementation  is  useful.  
 
LABORATORY  EVALUATION  OF  IRON  STATUS  
è Direct  Measures  
o Bone  marrow  aspiration  and  biopsy  
§ If   you   are   suspecting   hereditary  
hemochromatosis  
o Liver  biopsy  
è Indirect  Measures  
o Serrum   ferritin,   serrum   transferrin   receptor  
concentration  
o RBC,  zinc,  protoporphyrin  level  
o PBS   –   Microcytic,   hypochromic   red   cell*   may   1  
point  ka  na  daw  pag  kabisado  mo  ito.  
o Serum  Iron*  
o TOTAL  BINDING  CAPACITY  (TIBC)*  
o Transferrin  saturation*  
§ Serum  Iron  x  100  /  TIBC  
è *  -­‐  request  this  because  they  are  not  affected  by  infection  
 
è In  the  intestinal  lumen,  Fe3   enters  to  the  intestinal  mucosa    
by  undergoing  REDUCTION  facilitated  by  Ferric  reductase.    
è It   will   then   attach   to   the   DIVALENT   METAL   TRANSPORTER    
(DMT1)  which  facilitate  further  internalization  of  iron    
è Then  it  binds  to  FERROPORTIN,  after  oxidase  reduction  this    
will   then   be   released   to   the   plasma   and   then   transported    
to  the  cells.      
è However,  in  cases  that  there  is  an  increase  in  the  activity  of    
HEPCIDIN  the  FERROPORTIN  will  undergo  lysis.    
è If   HEPCIDIN   binds   to   the   FERROPORTIN,   the   release   of    
IRON   will   be   impeded   thus   will   not   be   in   the   circulating    
blood.    
è THE   IRON   that   is   released   in   the   blood   will   attach   to   the      
TRANSFERRIN  receptor.     (Figure:  Appearance  of  red  cell  in  Iron  Deficiency  Anemia)  
è The   Transferrin   will   then   facilitate   the   transport   of   IRON   to   è Don’t  be  confused  with  Thalassemia  
the  CYTOPLASM  of  the  CELL.   o Poikilocytosis  –  there’s  presence  of  TARGET  CELLS  
in  Thalassemia  
 

KIM  VILLANUEVA,  PTRP  (3A)   2  

 
EVOLUTION  OF  IRON  DEFICIENCY   è Serum  Transferrin:  2-­‐4  g/L  (1  g/L  transferrin  =  20umol/L  
binding  capacity)  
è Serum  Iron:  10-­‐30  u  mol/L;  TIBC:  40-­‐75  u  mol/L;  serum  
ferritin:  MALE,  40-­‐340u  g/L,  FEMALE:  14-­‐150  u  g/L)  
 
CAUSES  OF  IRON  DEFICIENCIES  
è Blood  Loss  
o GI  Bleeding,  GenitoUrinary  Tract  Bleeding,  Respi  
Tract,  Blood  Donation  
è Rapid  Growth  and  Devt  
è Menstruation  
è Pregnancy  
è Inadequate  Iron  Supply  
è Dietary  deficiency  
è Impaired  absorption  of  Iron  
 
CLINICAL  PRESENTATION  
è Asymptomatic  but  with  Lab  signs  of  IDA  
è Features  of  the  underlying  disorder  responsible  for  iron  
deficiency  
o If  there’s  blood  loss,  that’s  the  number  1  
complain  
o Post-­‐surgery  
è Non-­‐specific  manifestations  of  anemia  
o Dizziness,  headache,  hair  loss  
è Signs  and  sx  SPECIFIC  to  IDA  
o Pagophagia  
o Koilonychia  
o Blue  Sclera  
o Angular  cheilosis  
  o Plummer  Vinson’s  Syndrome  –  Esophageal  web,  
(FIGURE:  Lab  Studies  in  evolution  of  Iron  Deficiencies.  Take  note  of   dysphagia,  IDA  because  of  NODULAR  TOXIC  
the  GREEN  HIGHLIGHTED  PARTS  –  CONCENTRATE  ON  THIS  TABLE)   GOITER  
 
IRON  THERAPY  
IRON  DEFICIENCY:  Stages  of  development  
è Up  to  200mg  of  elemental  iron  per  day  is  given,  usually  as  
three  or  four  iron  tablets  
o Each  containing  50-­‐65  mg  elemental  iron  given  
over  the  course  of  the  day.  
è Ideally  iron  should  be  taken  on  an  empty  stomach  
è Reticulocyte  count  increases  within  4-­‐7  days  after  initiation  
of  therapy  (Reticulocytosis)  
è Sustained  treatment  for  a  period  of  6-­‐12  months  after  
correction  of  the  anemia  to  provide  stores  of  at  least  0.5-­‐1  
gram  of  IRON.  
NON-­‐RESPONSIVE  TO  IRON  THERAPY  
è Incorrect  diagnosis  
 
  è Continued  loss  of  iron  (occult  bleeding  etc)  
NORMAL  VALUES  OF  SERUM  IRON,  UIBC  and  SERUM  FERRITIN  in   è Chronic  infection  or  inflammation  
NORMAL  SUBJECTS,  IRON  DEFICIENCY  ANEMIA  and  ANEMIA  OF   è Mixed  deficiency  
CHRONIC  DISEASE  and  IRON  OVERLOAD   è Non-­‐compliance  of  the  patient  
  è Drug  perparation  
  SERUM  IRON/UIBC   SERUM  FERRITIN   è Malabsorption  of  Iron  
RATIO   QUESTION  NI  KAT  KABIGTING:  Gaano  katagal  maquantify?    
NORMAL   Serum  UIBC  is  more     ANSWER  NI  DOCTORA:  3-­‐4  weeks  of  OBSERVATION  is  needed.  If  the  
than  Serum  IRON   patient  is  non-­‐responsive,  check  the  factors  affecting  it.  
IRON  DEFICIENCY   Decreased  SERUM   Decreased    
IRON,  Increase  UIBC  
 
ANEMIA  OF  CHRONIC   Decreased  SERUM   Normal   PARENTERAL  IRON  THERAPY  is  given  if:  
DISEASE   IRON,  Decreased  UIBC   è Cannot  tolerate  the  side  effects  of  oral  iron  
IRON  OVERLOAD   Pure  SERUM  IRON   Over  1000   è PUD;  inflammatory  bowel  disease  
  è Cannot  comply  with  prescribed  dose  
è TIBC:  made  up  of  serum  iron  and  UIBC   è Iron  malabsorption  

KIM  VILLANUEVA,  PTRP  (3A)   3  

 
 è Conditions  with  rapid  loss  of  iron  from  continuous  bleeding    
which  cannot  be  compensated  by  oral  iron  (e.g.:    
Hereditary  telangiectasia)    
è FORMULA:  Body  weight  (kg)  x  2.3  x  (15-­‐patient’s    
hemoglobin,  g/dl)  +  500  or  1000  mg  (for  stores)    
è IV  Iron  dextran:  anaphylaxis    
o We  don’t  usually  use  this  because  of  anaphylaxis    
è Iron  sucrose  (Venofer)  is  used  because  of  its  less  adverse    
reactions.    
è Things  to  watch  out:  DO  A  TEST  DOSE.  Prior  to  infusion,    
give  meds  like  paracetamol  or  anti-­‐histamine.    
 
OTHER  HYPOPROLIFERATIVE  ANEMIAS    
1.  ANEMIA  OF  CHRONIC  DISEASE    
è Anemia  of  underproduction  that  is  usually:   (FIGURE:  PATHOPHYSIO  OF  ACD)  
o Normocytic,  normochromic    
o Mild  with  hemoglobin  level  above  10g/dL   2.  ANEMIA  OF  RENAL  DISEASE  
o In  30%  of  patients  anemia  can  be  severe  and  MCV   è NORMOCYTIC  NORMOCHROMIC  
is  reduced   o May  also  present  with  microcytic  
o Decrease  in  serum  iron  and  TIBC;  increase  serum   o Decreased  EPO  –  dec.  erythroid  committed  
ferritin   precursors  
o Decrease  transferrin  saturation.   o Effects  of  uremic  toxins  –  decrease  red  cell  
o FERRITIN  IS  ELEVATED,  SERUM  IRON  IS   survival  
DECREASED.   o Foliate  deficiency  
è It  can  be  microcytic  anemia  in  severe  cases   è Decreased  reticulocyte  count  
è OTHER  CAUSES:   è Hemolytic  anemia  
ASSOCIATED  DISEASES   ESTIMATED  PREVALENCE  
è Dilutional  anemia  
Infection  (acute  and  chronic)   18-­‐95%  
Cancer   30-­‐77%  
o Pinkish  appearance  upon  PE  and  yet  Hb  showed  
Autoimmune   8-­‐71%   decreased  value  (anemic)  
Chronic  Rejection  after  solid  organ   8-­‐70%   o Look  at  the  PBS  of  the  patient  
transplantation   è Blood  loss  anemia  
CKD  and  Inflammation   23-­‐50%   o Mechanically  induced  because  of  the  
CAUSES  OF  ACD   hemodialysis  
Block  in  reuse  of  iron  by  erythrocyte  
è 3.  ANEMIA  OF  ENDOCRINE  DISORDERS  
Shortened  erythrocyte  survival  
è è Mild  to  moderate  normocytic  normochromic  anemia  
Direct  inhibition  of  erythropoiesis  
è è A  decrease  in  plasma  volume  may  mask  the  severity  of  the  
Relative  deficiency  of  erythropoietin  
è anemia  
  è Results  of  decreased  O2  requirement  (e.g.  hypothyroidism)  
MECHANISM  OF  ANEMIA  IN  CHRONIC  INFLAMMATION   è Inappropriate  EPO  secretion  (e.g.  Adrenal  and  Androgen  
è Cytokine  driven  type  of  anemia  where  you  have  at  list  of   Deficiency)  
cytokines  that  is  known  to  inhibit  erythropoiesis  and  the   4.  ANEMIA  OF  LIVER  DISEASE  
release  of  erythropoietin   DIRECT  EFFECTS   INDIRECT  EFFECTS  
è TNK  and  interferon  gamma   Toxic  effects  of  ethanol   Dilutional  anemia  –  bec.  Of  Liver  
è These  cytokines  also  known  to  affect  hepcidin  –  decreases   failure  
Acute  and  chronic  blood  loss   Hypersplenism  –  enlargement  of  
absorption  in  the  GIT  
portal  veins,  portal  hypertension  
è Hepcidin  will  block  the  release  of  iron  by  macrophage     Hemolytic  anemia  (SPUR-­‐CELL)  –  10%  
è RBC  won’t  utilise  the  iron   of  patients  acquired  antibodies,  
è Because  it  is  cytokin  driven,  the  effect  of  the  cytokine  can   there’s  (+)  coomb’s  test  
be  over  drive  by  high  doses  of  erythropoietin     Malnutrition  
è ANEMIA  OF  CHRONIC  DISEASE  can  be  treated  by     Anemia  of  Chronic  inflammation  
erythropoietin    
SUPPRESION  OF  ERYTHROPOIESIS  BY  CYTOKINES    
   
   
   
   
   
   
   
   
   
 
 

KIM  VILLANUEVA,  PTRP  (3A)   4  

 
5.  ANEMIA  OF  MALIGNANCY    
è More  on  direct  effects    
DIRECT  EFFECTS   INDIRECT    
Replacement  of  marrow  by  malignant      
cells  (Myelopthisic),  Fibrosis    
Acute  and  chronic  blood  loss    
 
è Anemia  of  chronic  disease  
 
è Anemia  of  chronic  failure  
 
è Malnutrition    
è Microangiopathic  hemolysis  
 
è Immune  hemolytic  anemia  
 
   
TREATMENT  ASSSOCIATED  ANEMIA  
 
è Chemotherapy  
 
è Radiotherapy    
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
  SOURCE:  
 
PPT,  2015  Dra.  Perez  
 
Recording  
  RGAU  trans  2014  
 
 
 
 
  HI  NZG!  <3  you  
   
  GOOD  LUCK  SA  PRELIMS!  #RoadtoClerkship  
   
   
   
 
 
 
 
 
 
 
 

KIM  VILLANUEVA,  PTRP  (3A)   5