RBC Disorders - 2

Dr.CSBR.Prasad, M.D.,
Iron Deficiency Anemia
Importance of iron
Iron is quantitatively the most important
  bioactive element in human enzymology with
  roles in:
   – Oxygen transport and storage
   – Oxidative metabolism
   – Cellular growth and proliferation
Haem - Proteins
• Hemoglobin 70%
• Myoglobin 5%
• Tissue specific haem proteins
  –   Cytochromes Eg: P450
  –   Oxygenases
  –   Hydroxylases
  –   Peroxidase
  –   Catalase
  –   Ribonucleotide reductase
  –   Aconitase
Proteins of iron
         TRANSPORT & STORAGE
• TRANSFERRIN: Single chain glycoprotein with two
  iron binding sites, responsible for iron transport
  in plasma and extra-cellular fluid
• TRANSFERRIN RECEPTOR: Transmembrane
  glycoprotein with two transferrin binding sites
• FERRITIN: Spherical protein of 24 subunits which
  binds 4500 atoms of iron
• IRP: four domine cluster protein which co-
  ordinates translocational regualtion of iron
  proteins
Iron Distribution in Healthy
         Young Adults (mg)
Pool                     Men Women
Total                    3450   2450
Functional
 Hemoglobin              2100   1750
 Myoglobin               300    250
 Enzymes                 50     50
Storage
 Ferritin, hemosiderin   1000   400
Iron metabolism
Iron balance
Absorption                     Excretion
• 7mg/1000kcal                 • Exfoliated epithelial cells of
• 20-30% of haem iron is         the GI tract
  absorbed                     • Exfoliated cells of the skin
• <5% of non haem iron is      • Bile
  absorbed
• Absorption is increased by   • Urine
  aminoacids & ascorbic acid   • Menstrual blood loss
• Absorption is decreased by
  phytates, phosphates and        NO MECHANISM
  tannates
                                  FOR INCREASING
                                  IRON EXCRETION
Free iron is highly toxic
Hence, storage iron is sequestered
  – Ferritin or
  – Hemosiderin
Ferritin & Hemosiderin
• Ferritin is a ubiquitous protein-iron complex
• Highest levels :
   – liver, spleen, bone marrow, and skeletal muscles
• In the liver, most ferritin is stored within the
  parenchymal cells
• Partially degraded protein shells of ferritin
  aggregate into hemosiderin granules
• Since plasma ferritin is derived largely from the
  storage pool of body iron, its levels correlate well
  with body iron stores
Iron requirements
MEN                             WOMEN
• Daily basal iron loss         • Menstruating: 1.5mg/day
  <1mg/day                      • Pregnancy: 2mg/day or
• 10mg of iron in the diet        500mg for 280days of
  with 10% absorption is          gestation
  sufficient to maintain iron
  balance
Regulation of iron absorption
Iron absorption is regulated by
              HEPCIDIN
• Nature: Small peptide
• Source: Liver
• Stimulus: Intrahepatic iron level dictates
  Hepcidin synthesis
• Action:
  – Inhibits ferroportin
  – Hence, inhibits iron transfer from the enterocyte
    to plasma
Diseases with abnormal iron metabolism
         Basis: Alterations in hepcidin
• Anemia of chronic disease
• Mutations that disable TMPRSS6
• Primary and secondary hemochromatosis
  – Associated with mutations in hepcidin or the
    genes that regulate hepcidin expression
• Ineffective erythropoiesis suppresses hepatic
  hepcidin production, even when iron stores
  are high (unknown mechanim)
Prevalence of iron deficiency in India


      • Pregnant women 70-90%
      • Pre-school children 50%
Causes of iron deficiency
• Nutrional
  – Decreased dietary intake
  – Increased physiological demand
     • Pregnancy
     • Lactation
• Iron malabsorption           Chase the
• Blood loss                     cause
Causes of blood loss
 • Gastrointestinal
 • Pulmonary
   – Hemosiderosis
 • Urinary
   – Hematuria
   – Hemoglobinuria
 • Uterine
   – Menorrhagia
Causes of GI blood loss
• Esophagus        • Small intestine
   –   web            – Meckel’s divrticulum
   –   Varices        – Duodenal ulcer
   –   Reflux         – Crohn’s
   –   Carcinoma   • Large intestine
• Stomach             –   Polyps
   –   Ulcer          –   AV malformations
   –   Carcinoma      –   Carcinoma
   –   Leiomyoma      –   Ulcerative colitis
   –   Gastritis      –   Amebiasis
                      –   Tuberculosis
                      –   Hemorrhoids
Iron deficiency in children


• Most common between 1.5 to 4yrs
• Iron deficiency in children is so important
  because of the possibility that there may be
  irreversible impairment of cognitive skills
Blood and BM findings in IDA
Peripheral blood           Bone marrow
• <HGB                     • Erythroid hyperplasia
• <MCV                     • Micronormoblastic
• <MCH                       maturation
• Microcytic hypochromic   • Leucocytes and MKc may be
• Aniospoikilocytosis        normal
• Pencil shaped cells
• Tailed poikilocytes
• There may be
  Thrombocytosis
Microcytic hypochromic anemia of iron
 deficiency (peripheral blood smear)
Why anisocytosis in iron deficiency?


It’s due to differences in availability of iron in
       different areas of the bone marrow
Diagnosis of IDA
Laboratory evaluation of iron status
 •   Serum iron and iron binding capacity
 •   Serum ferritin
 •   Bone marrow iron status (Perl’s stain)
 •   Serum transferrin
 •   Plasma transferrin receptor
 •   RBC protoporphyrin
Serum transferrin receptor levels
• Good correlation with erythron mass
  – Increased in hemolytic anemia
• Good correlation with iron deficiency in which
  it’s increased
• Not increased in anemia of chronic disease
Important points
Regulation of fe balance is mainly by
            absorption
Ferritn levels < 12 is indicative of fe
              deficiency
“Chase the cause in bleeding”
Weakness in IDA is disproportionate to
             HGB levels
Iron loss is mainly thru…..
• Hair growth
• Skin desquamation
• Menstruation / blood loss
Role of acid in fe absorption
Common cause of anemia in children
How gastrectomy causes anemia?
• Low or no acid secretion
How GJ causes anemia (IDA)
Causes for chronic blood loss
External bleeding Vs bleeding in to the
      tissues and Fe deficiency
Occult colonic carcinoma -
• Ask for occult blood test on stool
Main causes for microcytic
  hypochromic anemia

  •   Iron deficiency anemia
  •   Thalassemia
  •   Sideroblastic anemia
  •   Anemia of chronic disease
Sequence of events in iron deficiency

At presentation           With treatment
• Disappearance of iron   • Disappearance of
   stores                   microcytosis
• Drop in hgb             • Raise in hgb
• Microcytosis            • Restoration of body iron
                            pool
END
Dr.CSBR.Prasad, M.D.,
Associate Professor of Pathology,
Sri Devaraj Urs Medical College,
         Kolar-563101,
           Karnataka,
             INDIA.
   csbrprasad@reiffmail.com

Rbc disorders 2

  • 1.
    RBC Disorders -2 Dr.CSBR.Prasad, M.D.,
  • 2.
  • 3.
    Importance of iron Ironis quantitatively the most important bioactive element in human enzymology with roles in: – Oxygen transport and storage – Oxidative metabolism – Cellular growth and proliferation
  • 4.
    Haem - Proteins •Hemoglobin 70% • Myoglobin 5% • Tissue specific haem proteins – Cytochromes Eg: P450 – Oxygenases – Hydroxylases – Peroxidase – Catalase – Ribonucleotide reductase – Aconitase
  • 5.
    Proteins of iron TRANSPORT & STORAGE • TRANSFERRIN: Single chain glycoprotein with two iron binding sites, responsible for iron transport in plasma and extra-cellular fluid • TRANSFERRIN RECEPTOR: Transmembrane glycoprotein with two transferrin binding sites • FERRITIN: Spherical protein of 24 subunits which binds 4500 atoms of iron • IRP: four domine cluster protein which co- ordinates translocational regualtion of iron proteins
  • 6.
    Iron Distribution inHealthy Young Adults (mg) Pool Men Women Total 3450 2450 Functional Hemoglobin 2100 1750 Myoglobin 300 250 Enzymes 50 50 Storage Ferritin, hemosiderin 1000 400
  • 7.
  • 8.
    Iron balance Absorption Excretion • 7mg/1000kcal • Exfoliated epithelial cells of • 20-30% of haem iron is the GI tract absorbed • Exfoliated cells of the skin • <5% of non haem iron is • Bile absorbed • Absorption is increased by • Urine aminoacids & ascorbic acid • Menstrual blood loss • Absorption is decreased by phytates, phosphates and NO MECHANISM tannates FOR INCREASING IRON EXCRETION
  • 9.
    Free iron ishighly toxic Hence, storage iron is sequestered – Ferritin or – Hemosiderin
  • 10.
    Ferritin & Hemosiderin •Ferritin is a ubiquitous protein-iron complex • Highest levels : – liver, spleen, bone marrow, and skeletal muscles • In the liver, most ferritin is stored within the parenchymal cells • Partially degraded protein shells of ferritin aggregate into hemosiderin granules • Since plasma ferritin is derived largely from the storage pool of body iron, its levels correlate well with body iron stores
  • 11.
    Iron requirements MEN WOMEN • Daily basal iron loss • Menstruating: 1.5mg/day <1mg/day • Pregnancy: 2mg/day or • 10mg of iron in the diet 500mg for 280days of with 10% absorption is gestation sufficient to maintain iron balance
  • 12.
  • 13.
    Iron absorption isregulated by HEPCIDIN • Nature: Small peptide • Source: Liver • Stimulus: Intrahepatic iron level dictates Hepcidin synthesis • Action: – Inhibits ferroportin – Hence, inhibits iron transfer from the enterocyte to plasma
  • 14.
    Diseases with abnormaliron metabolism Basis: Alterations in hepcidin • Anemia of chronic disease • Mutations that disable TMPRSS6 • Primary and secondary hemochromatosis – Associated with mutations in hepcidin or the genes that regulate hepcidin expression • Ineffective erythropoiesis suppresses hepatic hepcidin production, even when iron stores are high (unknown mechanim)
  • 15.
    Prevalence of irondeficiency in India • Pregnant women 70-90% • Pre-school children 50%
  • 16.
    Causes of irondeficiency • Nutrional – Decreased dietary intake – Increased physiological demand • Pregnancy • Lactation • Iron malabsorption Chase the • Blood loss cause
  • 17.
    Causes of bloodloss • Gastrointestinal • Pulmonary – Hemosiderosis • Urinary – Hematuria – Hemoglobinuria • Uterine – Menorrhagia
  • 18.
    Causes of GIblood loss • Esophagus • Small intestine – web – Meckel’s divrticulum – Varices – Duodenal ulcer – Reflux – Crohn’s – Carcinoma • Large intestine • Stomach – Polyps – Ulcer – AV malformations – Carcinoma – Carcinoma – Leiomyoma – Ulcerative colitis – Gastritis – Amebiasis – Tuberculosis – Hemorrhoids
  • 19.
    Iron deficiency inchildren • Most common between 1.5 to 4yrs • Iron deficiency in children is so important because of the possibility that there may be irreversible impairment of cognitive skills
  • 20.
    Blood and BMfindings in IDA Peripheral blood Bone marrow • <HGB • Erythroid hyperplasia • <MCV • Micronormoblastic • <MCH maturation • Microcytic hypochromic • Leucocytes and MKc may be • Aniospoikilocytosis normal • Pencil shaped cells • Tailed poikilocytes • There may be Thrombocytosis
  • 21.
    Microcytic hypochromic anemiaof iron deficiency (peripheral blood smear)
  • 22.
    Why anisocytosis iniron deficiency? It’s due to differences in availability of iron in different areas of the bone marrow
  • 23.
  • 24.
    Laboratory evaluation ofiron status • Serum iron and iron binding capacity • Serum ferritin • Bone marrow iron status (Perl’s stain) • Serum transferrin • Plasma transferrin receptor • RBC protoporphyrin
  • 25.
    Serum transferrin receptorlevels • Good correlation with erythron mass – Increased in hemolytic anemia • Good correlation with iron deficiency in which it’s increased • Not increased in anemia of chronic disease
  • 26.
  • 27.
    Regulation of febalance is mainly by absorption
  • 28.
    Ferritn levels <12 is indicative of fe deficiency
  • 29.
    “Chase the causein bleeding”
  • 30.
    Weakness in IDAis disproportionate to HGB levels
  • 31.
    Iron loss ismainly thru….. • Hair growth • Skin desquamation • Menstruation / blood loss
  • 32.
    Role of acidin fe absorption
  • 33.
    Common cause ofanemia in children
  • 34.
    How gastrectomy causesanemia? • Low or no acid secretion
  • 35.
    How GJ causesanemia (IDA)
  • 36.
  • 37.
    External bleeding Vsbleeding in to the tissues and Fe deficiency
  • 38.
    Occult colonic carcinoma- • Ask for occult blood test on stool
  • 39.
    Main causes formicrocytic hypochromic anemia • Iron deficiency anemia • Thalassemia • Sideroblastic anemia • Anemia of chronic disease
  • 40.
    Sequence of eventsin iron deficiency At presentation With treatment • Disappearance of iron • Disappearance of stores microcytosis • Drop in hgb • Raise in hgb • Microcytosis • Restoration of body iron pool
  • 41.
  • 42.
    Dr.CSBR.Prasad, M.D., Associate Professorof Pathology, Sri Devaraj Urs Medical College, Kolar-563101, Karnataka, INDIA. csbrprasad@reiffmail.com