Understanding Anemia

Anemia

• Anemia is when the Hemoglobin concentration is below the accepted normal range

Normal Ranges of Hemoglobin

• Female: 11.5 - 14.0 g/dL
• Male: 13.5 - 15.5 g/dL
• Lower levels in females is due to monthly blood loss and Estrogen
• Higher levels in males is due to higher muscle volume requiring more oxygen, and due to androgen hormone

Anemia - Clinical Features

• In anemia, there is a low supply of oxygen to the tissue, causing Hypoxia
• Symptoms and signs of anemia can include faster heartbeats, palpitations, and tachycardia
• Shortness of breath is related to a low number of oxygen-carrying units (RBCs and Hb concentration)
• Pallor, headache, fatigue, and weakness are also manifestations of anemia
• The body's adaptation mechanisms redistribute blood flow to tissues with higher oxygen dependency, such as the brain and heart
• Chronic blood loss causes less severe symptoms compared to acute blood loss due to compensation

Anemia - Lab Findings

• Red cell indices can help in identifying anemia and its type
• RBCs count for males should be 4.7-6.1 million cells/µL
• RBCs count for females should be 4.2-5.4 million cells/µL
• Hemoglobin for females should range from 11.5-14.0 g/dL
• Hemoglobin for males should range from 13.5-15.5 g/dL
• Normal MCV ranges from 80-100 fl
• Normal MCH ranges from 27-31 pg
• Normal MCHC ranges from 32-36 g/dl

Classification of Anemia

• Microcytic Hypochromic anemia is MCV < 80 fl and MCH < 27pg
• Iron deficiency, thalassemia, anemia of chronic diseases, sideroblastic anemia, and lead poisoning are all Microcytic Hypochromic anemias
• Normocytic Normochromic anemia is MCV 80-100 fl and MCH 27-31 pg
• Hemolytic anemias, anemia of chronic disease, after acute blood loss, mixed deficiencies, bone marrow failure, and renal disease are all Normocytic Normochromic anemias
• Microcytic anemia exhibits MCV > 100 fl
• Megaloblastic anemia (B12 or folate deficiency) and non-megaloblastic causes (alcohol, liver disease) are all Microcytic anemias

Etiology (Causes) of Anemia

• Causes include loss of red cells due to bleeding
• Increased destruction of RBCs, causing hemolytic anemia
• Failure of red blood cell production from the bone marrow is another cause
• Dilution of red cells by increased plasma volume, as seen in pregnancy, can lead to anemia
• Nutritional deficiencies of iron, Vitamin B12, or folate can cause anemia
• Failure of Bone marrow, causing Aplastic anemia, marrow infiltration, etc
• Ineffective red cell production, as seen in thalassemia

Microcytic Anemias & Iron Deficiency Anemia

• Iron deficiency anemia (IDA) is a microcytic anemia

The Importance of Iron in the Body

• Iron is crucial for hemoglobin synthesis and for making proteins and enzymes like cytochrome and catalase
• The body iron content typically ranges from 3 - 5 g
• The daily iron intake ranges from 10 - 20 mg, with only 1-2 mg being absorbed
• Absorption primarily occurs in the duodenum and jejunum
• Iron absorption regulation serves as the primary mechanism for controlling body iron content
• Hepcidin is the major regulator of iron homeostasis

Iron Homeostasis

• Daily diet contains 10-20mg iron
• 1-2mg Iron is absorbed per day
• Transferrin transports Iron
• 75% of Iron goes towards Hemoglobin/ Erythropoiesis
• 10-20% of Iron goes towards storage to the Liver and heart in the form of Ferritin
• There is no physiologic excretion mechanism for Iron

Three Types of Proteins Involved in Iron Homeostasis

• Transferrin protein binds two iron atoms and delivers iron to tissues, especially bone marrow (BM)
• Transferrin receptor "TfR1" is a Glycoprotein dimer expressed on all cells and provides access to iron bound transferrin into the cell
• Ferritin & hemosiderin are iron stored forms in the macrophage of RES that provides available tissue iron

Iron Deficiency Anemia (IDA)

• Hypochromic microcytic anemia due to a defect in hemoglobin synthesis from iron depletion
• Iron deficiency anemia is the common anemia worldwide
• Common in developing countries/ populations with malnutrition
• Anemia due to Iron Deficiency is caused by a reduction in the Hb synthesis within the RBCs, leading to a reduction in O2 delivery to the tissues

Mechanisms of Disease Causation in Iron Deficiency Anemia

• It develops gradually
• Reduction in the body content of Iron
  • Low iron intake
  • Low absorption
  • Increased Iron loss due to bleeding
  • Increased Iron Demands
• Complete depletion in Iron Storage in the form of Hemosiderin & Ferritin
• Causes a reduction in Hb synthesis, causing Anemia and reduced RBC synthesis
• Eventually causing Iron Deficiency Anemia (IDA)

Iron Deficiency Anemia Leads to

• Increased iron absorption from the duodenum to 20-30%
• Decreased hepcidin production
• Increases in TfR1

Causes of Iron Deficiency Anemia (IDA)

• Insufficient iron in the diet, particularly lacking red meat, which is the best source of dietary iron
• Poor iron absorption by the body due to conditions like enteropathy or gastrectomy
• Chronic blood loss such as GI tract or uterine bleeding with Ongoing blood loss, especially from menstruation (>80 ml blood loss at each cycle)
• Periods of rapid growth

High-Risk Groups for Iron Deficiency Anemia

• Women of child-bearing age with severe blood loss through menstruation.
• Pregnant and lactating women who need more iron to increase RBC mass for fetus transfer and blood loss during delivery.
• Infants, children, and adolescents in growth phases.
• People with a poor dietary intake of iron for a long time

Common Signs & Symptoms of Iron Deficiency Anemia

• Fatigue and Weakness
• Pale Skin
• Rapid Heartbeat
• Irritability
• Decreased appetite
• Dizziness or feeling lightheaded
• Visual disturbance

Specific Signs & Symptoms of Iron Deficiency Anemia

• Painless glossitis
• Angular Stomatitis
• Brittle, spoon nails (koilonychia)
• Dysphagia (Paterson-Kelly Syndrome)
• Unusual cravings (rarely)

Diagnosis of Iron Deficiency Anemia

1. CBC:

• Low RBC Count
• Low Hb
• Low PCV
• Low MCV
• Low MCH, MCHC
• High RDW

2. Blood Film Examination :

• Essential to identify all causes of anemia
• RBCs should show:
  • Hypochromic microcytic cells
  • Occasional target cells, pencil-shaped cells, & tear drop
• Anisocytosis
• Reticulocyte Count reduced

Additional Conditions

• Blood film may show dimorphic red cells if anemia proceeds for the following conditions:
  • Severe folate or VIT B12 deficiency
  • Iron therapy
  • Transfusion

Iron Profile Tests for Diagnosis of Iron Deficiency

• Serum iron is reduced, being less than 60 µg/dl
• TIBC level s increased, being higher than 240 µg/dl
• Saturated IBC shows a decreased level to less than 10%
• Serum ferritin is very low, being less than 12 mic/dl
• Serum transferrin receptor shows increased sTfR

Additional Notes On Iron Deficiency Diagnosis

• Bone marrow examination is not essential to diagnose IDA in all cases, except in difficult and complicated cases
• Iron stores can be absent inside Macrophages
• Small Normoblasts observed showing ragged cytoplasms
• In the Bone Marrow examination, Stains for Iron would be Negative stains for Perls

Treatment for Iron Deficiency

• The cause of the deficiency must be found first
• Then treat with Iron to increase the amount/ correct the anemia

1. Oral Iron supplements, mostly in Ferrous Sulphate form, with a dose of 67% iron/ 200 tablet, on empty stomach
2. Parenteral:

• Is used for specific clinical situations
• Is prescribed to patients that cant tolerate or absorb iron from GI.

Additional Types Of Microcytic Anemia

• Decreased release of iron from macrophages into the Pplasma, due to
  • Infections e.g. tuberculosis (TB)
  • Non-Infectious e.g. rheumatoid arthritis
  • Malignancy

Anaemia of Chronic Disorders - Lab Results

• Mild anemia
• Mildly reduced MCH/MCV
• Low serum Fe
• Low TIBC
• Normal or raised serum ferritin
• Fe stores normal
• Normoblast Fe reduced

Anemia of Chronic Disorders - Treatment

• Does not respond to Fe therapy
• Needs treatment of the disorder causing the anaemia

Sideroblastic Anemia - Causes

• 1- Hereditary, due to Congenital enzyme defect, e.g., lack of d-ALA synthetase or lack of haem synthetase
• 2- Acquired, from myelodysplasia from refractory MDS or Due to chemicals, e.g. lead, alcohol

Sideroblastic Anemia - Facts

• Exhibits problems with heme synthesis
• Shows raised levels serum Fe
• Normal levels of TIBC
• Raised levels of serum ferritin
• Ring Sideroblasts

Thalassaemia - About

• A genetic problem with the Globin synthesis that causes a-thalassaemia and b-thalassaemia
• A-Thalassemia is a reduced production of a-globin chains
• B-Thalassemia is a reduced production of b-globin chains
• Very importnat to differentiate to to Iron Defincency

Thalassaemia - Lab Results

• Exhibits normal or raised levels of serum Fe
• Norm or low levels of low TIBC
• Normal of raised levels of serum ferritin
• CBC parameter mostly shows high to differentiate from IDA
• Hb electrophoresis is is required to confirm the diagnosis

Differential Diagnosis of Microcytic Anemia

• MCV & MCH Reduced (in IDA, Thalassemai trait, Sideroblastic anemia)
• Serum Iron- Reduced (in IDA) and Raised (in Sideroblastic anemia)
• Serum Ferritin- Reduced (in IDA) and Raised (in Sideroblastic anemia)
• BM Iron Stores- Absent (in IDA, Thalassemai trait) and Present (in Sideroblastic anemia)

Summary Table

• IDA has reduced levels of Fe and reduced levels of serum ferritin, but increased TIBC, unlike other other conditions

Low Hemoglobin Algorithm

• Low Hemoglobin and MCV requires the measurement of Ferritin
• If measured Ferritin is low, then the subject has IRON Deficiency Anemia
• If Ferritin measured is Normal, the subject probably has Anemia of chronic disease and/ or Congenital Hb disorder
• Requires a Reticulocyte Count to narrow down to cause

Macrocytosis and Macrocytic Anemia

• Defined as RBCs with MCV > 100 fl.
• Diagnosied where Hb low 'anemia' and MCV is high"macrocytic"
• Causes can be categorized, i.e. Megaloblastic anemial and Non-Megaloblastic

Macrocytic Anemia - Possible Causes

• Alcoholism has a direct effect on the bone marrow
• Liver disease has target cells /leptocytes and acanthocytes that are common
• Reticulocytosis proceeds when there is a bleed or haemolysis in which Polychromasia is a feature with a high reticulocyte count
• Chronic hypoxia in Elderly smokers with COAD "chronic obstructive airways disease"
• Vitamin B12 Deficiency
• Folate Deficiency

Megaloblastic Anemia - About

• Disorder associated with defective DNA synthesis
• Cytoplasmic components are synthesized in large amount, while DNA synthesis is delayed
• Abnormal maturation in the bone marrow for
  • RBCs,
  • Granulocytes
  • Megakaryotypes.

Megaloblastic Anemia - Notes

• Impaired DNA synthesis will affect all dividing cells of the body
• So impaired DNA synthesis will be evident in these tissues first
• The patients will have symptoms in all these tissues, but blood is the easiest for analysis
• "megaloblastic anemia" affects DNA metabolism

Megaloblastic Anemia - Facts

• “Megaloblastic anemia" is name comes from the very large cells (blasts) of the BM, with distinctive morphology, due to the impairment of DNA synthesis.
• Impaired DNA synthesis is occurred due to:
  • Vitamin B12 deficiency
  • Folic Acid deficiency
• Therefore require a study and review of DNA synthesis to know the role of folic acid & vit B12 in this process.

Role Of Folate & Vitamin B12

• Folate & B12 are essential for producing thymidine nucleotide
• Thymidine nucleotide is one of the building blocks of the DNA (dATP, dCTP & dGTP)
• Vit B12 is co-enzyme for 2 biochemical reactions:
  • Conversion of homocysteine to methionine (folate cycle & DNA synthesis)
  • Conversion of methylmalonyl CoA to succinyl CoA (fatty acid oxidation)

Pathogenesis of Megaloblastic Anemia

• Production of thymidine nucleotide for DNA synthesis is impaired
• Homocysteine is accumulated
• Nonfunctional DNA affects cell division and leads to cell lysis and apoptosis
• Hence, leading to ineffective hematopoiesis (destruction of blast cells in the BM.

Vitamin B12 and its Properties

• Water-soluble vitamin, i.e. Cobalamin
• Sources include dietary and storage
  • Meat, eggs, milk and dairy products, fish & liver provide source
  • 1-2 μg is Daily required
  • Reqd. Absorption in the ileum
  • Storage of liver has 2-3 mg, enough for 2-4 years

Absorption of Vitamin B12

• Needs Intrinsic Factor (IF), a glycoprotein receptor for B12, secreted via stomach parietal cells
• IF-B12 complex binds a cubilin receptor, on ileal cells.
• Transcobalamin II (TC II): is reqd for transportation of B12 within blood to BM & other tissues.

Causes for Vitamin B12 deficiency

• Poor diet intake (rare), only in strict vegetarians
• “vegans" cause vitamin B12 Def
• Main cause of malabsorption (mostly) is Gastrectomy, ileal resection or Competitive Parasites Diphyllobothrium latum
• Increased need B12 in Pregnancy or infancy
• Pernicious anemia as another cause, where autoimmune disease leads to loss of IF ➔B-cells mediate destruction of gastric parietal cells

Folate - Information

• Water-soluble and available as Folic acid
• Sources of dietary can be Liver & meat, leafy green vegetables, cereals & other certain fruits that make “Most diet
• Daily requirement of 100-150 µg. & in the Ileum requires Absorption
• Transported in albumin, stored in liver for up to 4 months

Causes for Folate Deficiency

• Malabsorption, including diseases like inflammatory bowel disease and surgical
  • Often occurs in those with an overcooked diet
    • Overcooking vegetables
• Increased need of Folate in Pregnancy or Infancy - Increased during Pregnancy or Infancy if the deficiency rises for example by taking Drugs as impairment for the Folic acid metabolism

Clinical symptoms for Vitamin B12 & Folate Deficiency

• Lemon-yellow pallor skin or "mild jaundice" can derive because an As expect of any anemia, it can derive weakness or dizziness that is fatigue
• Smooth, sore tongue (glossitis)., where may B12 levels decreases, especially there is low platelet
• As there are purpura, a thrombocythenia will then be in addition Low WBC Count is recurrent
• There wil be Neurological problems

Clinical symptoms/Conditions

• Patients can show Numbness or tingling ➔ that will be derived in extremities and cause that the Memory Loss is caused
• Those patients that has a Dementia, difficulty levels ➔ that wil be show that in Walking the Confusions also is caused
• These neurological issues Unique to vitamin B12 deficiency that the other will not
• Causes Neural tube be damaged for the Deficits

Incidences and Statistics

• Megaloblastic Anemia has neural Tube that is common among population of north European that their ratio are also 1:2 in male to female, the

Laboratory Diagnosis

• COMPLETE BLOOD COUNT (CBC) will show Reduced Hb/ RCC, Hematocrit levels
• MCV/MCH is is an increased value , RDW and Plt is Decreased while low levels is noticed in WBCs as also
• This results the PANCYTOPENIA ➔ where are all the bloods wil show a decreased value

Laboratory tests on Bloods Diagnosis

• PERIPHERAL BLOOD Morphology that we can analysis ➔ the cells for their Erythrocytes or also the other testings

Erythrocytes tests (Laboratory results)

• Tests show Macrocytic that the norms of the Morphochromic
• Also shows how that Target ➔ for which cell that could show for the test and if so there for the Schistocyte then we see for how that basophilic

Tests

• Hypercellularity in Bone ➔ shows tests like Megalobastic and all these tests

Confim and Show Tests

• Then shows for tests which shows that B12 level with Confirmatory of that for testing with their B12 deficiency
• When is show low ➔for with as low level with the Schilling

Folate Tests

• Show or Confirms levels for Folic acid deficiency
  • When Serum folate is used to assay is in the low value form because that this would indicate and will indicates for testing the amount for the RBCs with its low level that helps to estimate is how better that there will be.

Treatment Of Vit. B12 + Folate Deficiency

• Vitamin B12: that with the IM or Orally
• Folate: is taken Orally

Lab tests and Erythrocytes with the norm with the chromatic anemia

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Lab and Its Values

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