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ANEMIA - MBBS 1st Year Physiology

Long Answer Notes (Exam-Oriented)

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DEFINITION

• Hemoglobin (Hb) concentration, or
• Red blood cell (RBC) count, or
• Packed cell volume (PCV/Hematocrit)

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NORMAL RED CELL PHYSIOLOGY (Basis for Understanding Anemia)

RBC Production (Erythropoiesis)

• Site: Bone marrow (red marrow) in adults; liver and spleen in fetal life
• Normal RBC lifespan: 120 days
• After destruction, old RBCs are phagocytosed by macrophages in spleen, liver, and bone marrow (mononuclear phagocyte system)

Regulation by Erythropoietin (EPO)

• Primary regulator of red cell production is effective oxygen delivery to tissues
• When anemia causes decreased O2 tension in renal cortex, the transcription factor HIF (Hypoxia-Inducible Factor) is activated
• HIF upregulates EPO production (predominantly from kidney; liver retains minor capacity)
• EPO binds specific receptors on erythroid progenitors in bone marrow --> increased RBC production
• When anemia is corrected and O2 tension normalizes, EPO falls back to basal levels

Iron Metabolism (Key for MCQs and Long Answers)

• Total body iron: ~3.5 g (male), ~2.5 g (female)
• ~80% is functional (hemoglobin, myoglobin, iron-containing enzymes - catalase, cytochromes)
• ~15-20% is in storage form: ferritin and hemosiderin (macrophages of liver, spleen, bone marrow)
• Iron transport in plasma: bound to transferrin (normally ~33% saturated; serum iron ~120 µg/dL in men, ~100 µg/dL in women)
• Daily iron loss: 1-2 mg/day (shed mucosal and skin epithelial cells) - must be balanced by absorption

1. Dietary iron reduced (Fe3+ → Fe2+) by duodenal cytochrome B (ferric reductase)
2. Fe2+ enters enterocyte via DMT-1 (divalent metal transporter-1)
3. Fe2+ exported from enterocyte basolaterally via ferroportin
4. Oxidized by hephaestin/ceruloplasmin back to Fe3+ to bind transferrin in plasma

• Small peptide secreted by liver; negatively regulates ferroportin
• When iron stores rise: HFE protein on hepatocytes senses high iron → upregulates hepcidin → ferroportin blocked → less iron absorbed
• Inflammation (IL-6) → stimulates hepcidin → iron sequestration (basis of anemia of chronic disease)
• Erythroferrone (from erythroblasts in bone marrow) → suppresses hepcidin → more iron available for erythropoiesis

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CLASSIFICATION OF ANEMIA

A. Morphological Classification (MCV-Based) - Most Commonly Tested

B. Etiological Classification

• Iron deficiency
• Vitamin B12 / Folate deficiency (megaloblastic)
• Aplastic anemia
• Anemia of chronic inflammation/disease
• Anemia of CKD (EPO deficiency)

• Intracorpuscular: hereditary spherocytosis, G6PD deficiency, sickle cell disease, thalassemia
• Extracorpuscular: autoimmune hemolytic anemia, malaria, mechanical trauma (prosthetic valves)

• Acute: trauma, surgery
• Chronic: GI bleeding, menorrhagia

C. Pathophysiological Classification (Based on Reticulocyte Response)

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COMPENSATORY MECHANISMS IN ANEMIA

1. Cardiovascular: Increased heart rate, increased stroke volume, increased cardiac output (CO); blood redistributed to critical organs (brain, heart, liver, kidneys)
2. Shift in Oxyhemoglobin Dissociation Curve:
   • Anemia → increased 2,3-DPG (2,3-diphosphoglycerate) in RBCs
   • 2,3-DPG causes right shift of OxyHb curve → decreased O2 affinity → O2 more readily released to tissues
   • Right shift also caused by: acidosis, hypercapnia, hyperthermia
3. Increased Erythropoiesis: EPO released → stimulates bone marrow → reticulocytosis (rise seen 5-7 days after acute hemorrhage)
4. Plasma volume expansion: Dilutional compensation

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TYPES OF ANEMIA (Detailed)

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1. IRON DEFICIENCY ANEMIA (IDA)

Etiology / Causes:

• Inadequate intake: poverty, vegetarian diet, infants on milk diet
• Increased demand: pregnancy (each term delivery costs ~800 mg maternal iron), lactation, adolescent growth spurt
• Chronic blood loss: menorrhagia (most common cause in women of reproductive age), GI bleed (peptic ulcer, hookworm infection - major cause in developing world), hemorrhoids
• Malabsorption: celiac disease, post-gastrectomy

Pathophysiology (Stages of IDA):

Laboratory Findings:

• Hb and hematocrit ↓
• MCV ↓ (microcytosis)
• MCHC ↓ (hypochromia)
• Serum iron ↓
• TIBC (Total Iron Binding Capacity) ↑ (elevated transferrin)
• Serum ferritin ↓ (most sensitive early marker)
• Transferrin saturation <15%
• Hepcidin ↓ (reduced iron stores inhibit hepcidin synthesis)
• Peripheral smear: hypochromic microcytic RBCs, poikilocytosis (pencil cells, target cells)
• Reticulocyte count: low (hypoproliferative)

Clinical Features:

• Fatigue, weakness, pallor (conjunctival, palmar creases, nail beds)
• Palpitations, tachycardia
• Systolic ejection murmur (flow murmur due to increased cardiac output)
• Dyspnea on exertion

• Koilonychia (spoon-shaped nails)
• Pica - craving for non-food substances: clay, ice (pagophagia), dirt; pathognomonic for iron deficiency
• Restless leg syndrome
• Alopecia (hair loss)
• Atrophic glossitis (smooth, sore tongue)
• Angular cheilitis (painful cracks at corners of mouth)
• Dysphagia - esophageal web (Plummer-Vinson syndrome = dysphagia + microcytic anemia + atrophic glossitis)

Treatment:

• Oral iron supplementation (ferrous sulfate) → reticulocytosis in 5-7 days → Hb starts rising
• Treat underlying cause

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2. MEGALOBLASTIC ANEMIA (Vitamin B12 / Folate Deficiency)

Mechanism:

• Both B12 and folate are essential for DNA synthesis
• Deficiency → impaired DNA synthesis → cells cannot divide → nucleus remains large while cytoplasm matures normally
• Result: large cells with immature nuclei (megaloblasts in marrow; macro-ovalocytes in blood)
• Hypersegmented neutrophils (≥5 lobes) - hallmark on peripheral smear

Vitamin B12 Deficiency (Pernicious Anemia)

• Pernicious anemia: Autoimmune destruction of gastric parietal cells → lack of Intrinsic Factor (IF) → no IF-B12 complex → no absorption in terminal ileum (most common cause in adults)
• Strict vegetarian/vegan diet (B12 only in animal products)
• Gastric resection (loss of parietal cells)
• Terminal ileum resection/disease (Crohn's disease)

• Subacute combined degeneration of the spinal cord (SACD) - demyelination of posterior and lateral columns
• Features: loss of vibration and position sense, ataxia, UMN signs
• Neuropsychiatric symptoms: memory loss, irritability, depression
• Important: Folate therapy corrects hematological changes but does NOT prevent/may worsen neurological damage in B12 deficiency - always exclude B12 deficiency before starting folate

• Serum B12 ↓
• Serum methylmalonic acid ↑ (specific for B12 deficiency, normal in folate deficiency)
• Serum homocysteine ↑ (elevated in BOTH B12 and folate deficiency)
• MCV ↑ (macrocytosis)
• Hypersegmented neutrophils on smear
• Schilling test (historical): tests for IF-dependent B12 absorption

Folate Deficiency

• Poor diet (alcoholics, elderly, infants)
• Increased demand: pregnancy (prophylactic folic acid 5 mg/day recommended)
• Malabsorption: celiac disease
• Drug-induced: methotrexate (inhibits dihydrofolate reductase), phenytoin, trimethoprim

• Serum homocysteine ↑
• Methylmalonic acid: NORMAL (distinguishes from B12 deficiency)
• No neurological changes

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3. HEMOLYTIC ANEMIA

Classification:

• Intracorpuscular (intrinsic): defect within the RBC itself
  • Membrane defects: Hereditary spherocytosis, elliptocytosis
  • Enzyme defects: G6PD deficiency, Pyruvate kinase deficiency
  • Hemoglobin defects: Sickle cell disease, Thalassemia
• Extracorpuscular (extrinsic): normal RBC destroyed by external factors
  • Immune: Autoimmune hemolytic anemia (AIHA), transfusion reactions
  • Mechanical: Microangiopathic hemolytic anemia (MAHA), prosthetic heart valves
  • Infectious: Malaria

Common Lab Findings in ALL Hemolytic Anemias:

• Hb ↓, normocytic normochromic (usually)
• Reticulocytosis (hallmark - bone marrow compensating)
• Unconjugated (indirect) bilirubin ↑ → jaundice
• LDH ↑ (released from lysed RBCs)
• Haptoglobin ↓ (binds free Hb; consumed during hemolysis)
• Peripheral smear: fragmented RBCs (schistocytes) in mechanical hemolysis; spherocytes in hereditary spherocytosis/AIHA

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4. APLASTIC ANEMIA

• Idiopathic (most common, ~70%; autoimmune T-cell mediated destruction of stem cells)
• Drugs: chloramphenicol, benzene, cytotoxic drugs
• Radiation
• Infections: viral hepatitis, EBV, parvovirus B19

• Hypocellular (fatty) bone marrow on biopsy (pathognomonic)
• Normocytic normochromic anemia
• Low reticulocyte count (bone marrow not responding)
• Pancytopenia symptoms: anemia + infections (neutropenia) + bleeding (thrombocytopenia)

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5. ANEMIA OF CHRONIC DISEASE (Anemia of Inflammation)

• Inflammation → IL-6 → liver produces more hepcidin
• Hepcidin blocks ferroportin → iron trapped in macrophages → iron unavailable for erythropoiesis
• EPO levels inappropriately low (directly suppressed by inflammatory cytokines)
• Net result: RBC precursors starved for iron despite abundant storage iron

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CLINICAL FEATURES OF ANEMIA (General)

Symptoms:

• Fatigue, weakness, easy tiredness
• Palpitations (increased heart rate)
• Dyspnea on exertion
• Headache, poor concentration
• Pica (specific to iron deficiency)

Signs:

• Pallor: most reliable at conjunctival mucosa (Hb < 9 g/dL) and palmar creases (Hb < 7-8 g/dL)
• Tachycardia
• Systolic ejection murmur (flow murmur - increased CO)
• Peripheral edema (moderate-severe anemia - high output failure + reduced oncotic pressure)
• Retinal hemorrhages (severe anemia)
• All cardiovascular/vascular signs resolve with correction of anemia

Jaundice: specific to hemolytic anemia

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INVESTIGATIONS APPROACH (Exam Important)

Step 1: CBC + Peripheral Blood Smear

• Hb, PCV, MCV, MCH, MCHC, RDW
• Peripheral smear: cell morphology, WBC count, platelet count

Step 2: Reticulocyte Count

• Low → hypoproliferative (iron deficiency, megaloblastic, aplastic, anemia of chronic disease)
• High → hyperproliferative (hemolysis, acute blood loss)

Step 3: Based on MCV

• Microcytic: serum iron, TIBC, ferritin, peripheral smear, Hb electrophoresis
• Macrocytic: serum B12, folate, bone marrow examination
• Normocytic: reticulocyte count → if high: hemolysis screen (LDH, bilirubin, haptoglobin, Coombs test); if low: bone marrow biopsy

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SUMMARY TABLE FOR QUICK REVISION

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IMPORTANT EXAM POINTS (Don't Miss)

1. Pica (especially pagophagia - craving for ice) is pathognomonic of iron deficiency
2. 2,3-DPG increases in anemia → right shift of OxyHb curve → O2 released more easily to tissues (adaptive mechanism)
3. Hepcidin is the master regulator of iron homeostasis; elevated in ACD, reduced in IDA
4. MMA (methylmalonic acid) is elevated ONLY in B12 deficiency, NOT in folate deficiency - key diagnostic differentiator
5. Reticulocyte count is the single most important test to classify anemia as hypoproliferative vs. hyperproliferative
6. In pernicious anemia: give B12 IM (not oral) because the problem is lack of intrinsic factor for absorption
7. Aplastic anemia: hypocellular (fatty) marrow is diagnostic; pancytopenia is the presentation
8. Plummer-Vinson syndrome = iron deficiency anemia + dysphagia + atrophic glossitis (esophageal web)
9. Folate supplementation in a B12-deficient patient corrects blood count but can precipitate/worsen neurological damage - always rule out B12 deficiency first
10. Each full-term pregnancy consumes approximately 800 mg of maternal iron

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ANEMIA - MBBS 1st Year Physiology Notes

From Guyton & Hall Textbook of Medical Physiology (14th Ed.)

Long Answer Exam Format

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CHAPTER REFERENCE: "Red Blood Cells, Anemia, and Polycythemia" (Chapter 33, p. 440)

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1. RED BLOOD CELLS (ERYTHROCYTES) - Normal Physiology

Functions of RBCs

1. Primary function: Transport hemoglobin, which carries O2 from lungs to tissues
   • In humans, Hb must remain inside RBCs because if free in plasma, ~3% leaks through capillary membranes into tissue spaces or through the glomerular membrane into urine each pass through capillaries
2. CO2 transport: RBCs contain large quantities of carbonic anhydrase, which catalyzes the reversible reaction: CO2 + H2O ⇌ H2CO3 (at thousands of times the uncatalyzed rate). This allows blood to transport enormous CO2 as bicarbonate (HCO3-)
3. Acid-base buffering: Hemoglobin is an excellent acid-base buffer; RBCs account for most buffering power of whole blood

Shape and Size

• Biconcave disc
• Diameter: ~7.8 µm; thickness: 2.5 µm at thickest, ~1 µm at center
• Volume: 90-95 cubic micrometers
• The biconcave shape gives excess membrane for the contents inside, allowing the cell to deform without rupture as it squeezes through capillaries

Normal Values (Guyton)

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2. PRODUCTION OF RED BLOOD CELLS (Erythropoiesis)

Sites of Production at Different Ages (Guyton Table - important for exams)

Genesis: Stem Cell Pathway

• All blood cells originate from multipotent hematopoietic stem cells in the bone marrow
• These divide and differentiate into committed progenitor cells
• Committed progenitor for RBCs = CFU-E (Colony-Forming Unit - Erythrocyte)
• Differentiation sequence: Proerythroblast → Basophil erythroblast → Polychromatophil erythroblast → Orthochromatic erythroblast → Reticulocyte → Mature RBC

Erythropoietin (EPO) - The Key Regulator

• Produced by kidneys (primary site, ~90%) and liver (~10%)
• Stimulus for EPO release: Tissue hypoxia (any cause - anemia, high altitude, pulmonary disease, cardiac failure)
• When O2 delivery to kidney falls → EPO secretion increases → stimulates:
  • Increased production of proerythroblasts from stem cells
  • Increased rate of each stage in the development series
  • Accelerated release of reticulocytes into blood
• Provides a negative feedback loop: corrected O2 delivery → EPO falls back to basal levels
• Testosterone also stimulates EPO production (explains why men have higher Hb than women)

Requirements for Normal Erythropoiesis

• Essential for heme synthesis (porphyrin ring + Fe²⁺)
• Absorbed in duodenum; transported in plasma bound to transferrin
• Stored in liver, spleen, and bone marrow as ferritin and hemosiderin
• When iron stores are deficient → deficient hemoglobin formation → pale (hypochromic), small (microcytic) RBCs

• Both essential for DNA synthesis (specifically formation of thymidine triphosphate, a building block of DNA)
• Deficiency → failure of nuclear maturation and cell division
• Erythroblasts fail to proliferate rapidly and produce large, irregular, oval RBCs called macrocytes
• These macrocytes are fragile, have abnormal membranes, and survive only 1/2 to 1/3 of normal 120-day lifespan → maturation failure anemia

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3. HEMOGLOBIN FORMATION

• Synthesis begins in polychromatophil erythroblasts and continues into the reticulocyte stage (reticulocytes continue forming Hb for ~1 more day in circulation)
• Pathway:
  • Succinyl-CoA (from Krebs cycle) + glycine → porphyrin ring
  • Porphyrin + Fe²⁺ → Heme
  • Heme + globin chain → hemoglobin chain
  • 2 alpha + 2 beta chains → Hemoglobin A (adult Hb, HbA)

Types of Hemoglobin

O2-Carrying Capacity

• Each Hb molecule carries 4 molecules of O2 (one per heme group)
• Each gram of Hb combines with 1.34 mL of O2
• Normal blood with 15 g Hb/100 mL carries about 20 mL O2/100 mL blood (when fully saturated)

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4. DESTRUCTION OF RED BLOOD CELLS

• Normal RBC lifespan: 120 days
• Aging RBCs become progressively more fragile, with denatured proteins and stiffened membranes
• Old RBCs are destroyed by macrophages (tissue macrophages of the mononuclear phagocyte system - spleen most important)
• After destruction, hemoglobin is broken down:
  • Globin → amino acids (recycled)
  • Iron → stored as ferritin/hemosiderin (recycled for new Hb synthesis)
  • Porphyrin ring → converted to bilirubin → released into blood → taken up by liver → conjugated → excreted in bile

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5. ANEMIA - DEFINITION

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6. CAUSES / CLASSIFICATION OF ANEMIA (Guyton)

A. Blood Loss Anemias

• Rapid acute blood loss: body replaces plasma within 1-3 days but RBC replacement takes weeks → normocytic normochromic anemia initially
• Chronic blood loss: continued drain on iron stores → ultimately iron deficiency → microcytic hypochromic anemia

B. Aplastic Anemia (Bone Marrow Depression)

• Loss of bone marrow function → failure to produce RBCs
• Causes:
  • X-ray or gamma ray radiation (most common physical cause)
  • Industrial chemicals (benzene, insecticides)
  • Drugs: chloramphenicol, sulfonamides, phenylbutazone, anticancer drugs
  • Autoimmune T-cell destruction of stem cells
• Results in pancytopenia (all blood cells are decreased)
• Bone marrow becomes fatty (replaced by fat cells) - this is pathognomonic

C. Maturation Failure Anemias

i. Deficiency of Vitamin B12 → Pernicious Anemia

• Most common cause: atrophic gastric mucosa → failure to produce intrinsic factor (IF)
• Mechanism of B12 absorption (Guyton):
  1. Parietal cells of gastric glands secrete intrinsic factor (a glycoprotein)
  2. IF binds tightly with vitamin B12 in food, protecting it from digestion
  3. IF-B12 complex binds to specific receptor sites on brush border of ileal mucosal cells
  4. B12 is transported into blood by pinocytosis
• When IF is absent (pernicious anemia), B12 cannot be absorbed
• B12 is stored in liver in large amounts; minimum daily requirement is only 1-3 µg/day; stores last 3-4 years → that's how long before symptoms appear after IF loss
• Produces large, irregular, oval macrocytes (macrocytic anemia) with short lifespan

ii. Deficiency of Folic Acid

• Sources: green vegetables, fruits, meats (especially liver)
• Easily destroyed during cooking
• Malabsorption (e.g., sprue/celiac disease) is a major cause
• Same hematological picture as B12 deficiency (macrocytic), but no neurological damage

D. Hemolytic Anemias

• RBCs are fragile and rupture easily → cells destroyed faster than they are formed
• Even with increased production, severe anemia results

i. Hereditary Spherocytosis

• RBCs are small and spherical (not biconcave disc)
• Lack the normal loose, bag-like cell membrane structure
• Cannot withstand compression forces in splenic pulp and tight vascular beds → easily ruptured
• Leads to extravascular hemolysis

ii. Sickle Cell Anemia

• Caused by an abnormal beta chain in hemoglobin → Hemoglobin S (HbS)
• When exposed to low O2 concentrations, HbS precipitates into long crystals inside the RBC
• Crystals elongate the cell into a sickle shape
• Precipitated Hb damages cell membrane → cells become highly fragile → severe anemia
• Sickle cell crisis: Low O2 → sickling → RBC rupture → more hypoxia → more sickling (vicious circle)
  • Characterized by acute pain from vascular occlusion (plugging of small vessels by sickled cells)
  • Can cause rapid decrease in RBCs within hours and target organ injury/death

iii. Erythroblastosis Fetalis

• Rh-positive RBCs of fetus attacked by anti-Rh antibodies from Rh-negative mother
• Antibodies make cells fragile → rapid rupture → severe anemia in newborn
• Extremely rapid RBC production causes blast forms (erythroblasts) to appear in peripheral blood (hence the name)

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7. EFFECTS OF ANEMIA ON CIRCULATORY SYSTEM (Guyton - Key Exam Topic)

Pathophysiology of Cardiovascular Compensation

• Blood viscosity depends largely on RBC concentration
• In severe anemia, blood viscosity may fall to 1.5× water (normal ~3× water)
• Reduced viscosity → decreased peripheral vascular resistance → more blood flows through tissues → increased venous return to heart

• Hypoxia from reduced O2 transport → peripheral tissue blood vessels dilate
• Further increases return of blood to heart

• Combined effect of low resistance + vasodilation → cardiac output increases 3 to 4 times normal in severe anemia
• Heart pumps more blood per minute to compensate for reduced O2 per unit volume of blood

• Tachycardia (increased heart rate)
• Increased pulse pressure, bounding pulse
• Systolic flow murmur (due to turbulent flow from increased CO and reduced viscosity)
• Cardiac hypertrophy (long-standing anemia)
• High-output cardiac failure in severe/prolonged anemia

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8. POLYCYTHEMIA (for Contrast - Often Asked With Anemia)

• Secondary polycythemia: Normal response to hypoxia (high altitude, cyanotic heart disease) - EPO increases → RBC production increases
• Primary polycythemia (Polycythemia Vera): Cancerous condition of stem cells → uncontrolled RBC production
  • Hematocrit may rise to 60-70% (normal 40-45%)
  • Blood becomes extremely viscous → sluggish flow through microcirculation
  • Increased tendency for blood clot formation

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9. SUMMARY DIAGRAM: ANEMIA CLASSIFICATION (Guyton Framework)

                        ANEMIA
                           |
        ┌──────────────────┼─────────────────────┐
        │                  │                      │
   Blood Loss          Bone Marrow          Hemolytic
   Anemia              Failure               Anemia
   (Normocytic)        (Aplastic)            (Normocytic)
                           │                Hereditary
                   Maturation Failure       Spherocytosis
                           │                Sickle Cell
                    ┌──────┴──────┐         Erythroblastosis
                 B12/IF       Folic Acid
                Deficiency    Deficiency
               (Pernicious)   (Macrocytic)
                (Macrocytic)

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10. KEY EXAM POINTS FROM GUYTON (Don't Miss)

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11. PREVIOUS EXAM LONG ANSWER FORMATS

"Write a note on Anemia and its effects on the cardiovascular system"

"Describe the role of erythropoietin in regulation of RBC production. How is it altered in anemia?"

"Describe pernicious anemia / Maturation failure anemia"

"Classify anemia. Describe hemolytic anemia with examples"

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