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Your images cover these related hematology topics:
-
Pernicious anemia and vitamin B12 absorption
- Autoantibodies against intrinsic factor and parietal cells
- Schilling test concept and how to localize the cause of B12 malabsorption
-
Hemolytic anemia: basic classification
- Intracorpuscular versus extracorpuscular causes
- Intravascular versus extravascular hemolysis
- Consequences such as reticulocytosis, jaundice, splenomegaly, and marrow hyperplasia
-
Red-cell membrane structure
- Membrane skeleton proteins: ankyrin, spectrin, band 3, protein 4.1/4.2, actin, stomatin, glycophorins, and bilayer lipids
- Their roles in RBC shape, flexibility, and stability
-
Inherited RBC membrane disorders
- Hereditary spherocytosis
- Hereditary elliptocytosis
- Hereditary stomatocytosis and pyropoikilocytosis
At a high level, pernicious anemia is an autoimmune cause of B12 deficiency: intrinsic factor is absent or ineffective, so B12 cannot be absorbed normally in the terminal ileum. Hemolytic anemia means RBC survival is shortened, and the marrow compensates by increasing red-cell production. When the RBC membrane skeleton is defective, cells lose flexibility or membrane surface area and are commonly removed by splenic macrophages, causing mainly extravascular hemolysis.
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Your images cover these related hematology topics:
-
Pernicious anemia and vitamin B12 absorption
- Autoantibodies against intrinsic factor and parietal cells
- Schilling test concept and how to localize the cause of B12 malabsorption
-
Hemolytic anemia: basic classification
- Intracorpuscular versus extracorpuscular causes
- Intravascular versus extravascular hemolysis
- Consequences such as reticulocytosis, jaundice, splenomegaly, and marrow hyperplasia
-
Red-cell membrane structure
- Membrane skeleton proteins: ankyrin, spectrin, band 3, protein 4.1/4.2, actin, stomatin, glycophorins, and bilayer lipids
- Their roles in RBC shape, flexibility, and stability
-
Inherited RBC membrane disorders
- Hereditary spherocytosis
- Hereditary elliptocytosis
- Hereditary stomatocytosis and pyropoikilocytosis
At a high level, pernicious anemia is an autoimmune cause of B12 deficiency: intrinsic factor is absent or ineffective, so B12 cannot be absorbed normally in the terminal ileum. Hemolytic anemia means RBC survival is shortened, and the marrow compensates by increasing red-cell production. When the RBC membrane skeleton is defective, cells lose flexibility or membrane surface area and are commonly removed by splenic macrophages, causing mainly extravascular hemolysis.
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pernicious anemia AND hemolytic anemia
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Merck Manual pernicious anemia hemolytic anemia hereditary spherocytosis
1. Pernicious anemia
Pernicious anemia is an autoimmune cause of vitamin B12 deficiency.
Normal B12 absorption
- Dietary B12 binds to proteins in food.
- In the stomach, B12 later binds intrinsic factor (IF), a protein made by gastric parietal cells.
- The B12-IF complex is absorbed in the terminal ileum.
What goes wrong in pernicious anemia?
Autoimmune gastritis damages parietal cells and may produce antibodies against intrinsic factor.
| Antibody | Effect |
|---|---|
| Anti-intrinsic factor blocking antibody | Prevents B12 from binding intrinsic factor. |
| Anti-intrinsic factor binding antibody | Binds the IF-B12 complex and prevents its uptake by ileal receptors. |
| Anti-parietal cell antibody | Causes chronic atrophic gastritis, loss of parietal cells, reduced acid and intrinsic-factor production. |
Therefore:
Autoimmune parietal-cell injury → ↓ intrinsic factor → failure of terminal-ileal B12 absorption → B12 deficiency → megaloblastic anemia ± neurologic disease.
Typical findings include macrocytosis, hypersegmented neutrophils, high LDH, indirect hyperbilirubinemia, raised methylmalonic acid and homocysteine, glossitis, and sometimes paresthesia or gait impairment.
Schilling test
Your notes describe the historical Schilling test. It is now largely obsolete because radiolabeled B12 testing is rarely available.
Its original interpretation:
- Stage I: Oral radiolabeled B12 plus an intramuscular dose of non-radioactive B12. Normal people excrete an adequate proportion of the radiolabeled B12 in urine, traditionally >8% over 24 hours.
- Stage II: Repeat with oral intrinsic factor.
- Urinary excretion becomes normal: pernicious anemia / intrinsic-factor deficiency.
- Remains abnormal: another cause of malabsorption is likely.
- Terminal ileal disease or resection: B12 cannot be absorbed even when intrinsic factor is supplied.
- Pancreatic insufficiency: pancreatic enzymes may restore absorption in some cases, because they help transfer B12 from binding proteins to intrinsic factor.
- Bacterial overgrowth: may improve after antibiotics.
Today, diagnosis usually uses serum B12, methylmalonic acid, anti-intrinsic-factor antibodies, and assessment for autoimmune atrophic gastritis. As noted in Merck's anemia evaluation, intrinsic-factor antibodies support pernicious anemia.
2. Hemolytic anemia
Hemolytic anemia means RBCs are destroyed faster than the bone marrow can replace them.
Normal RBC life span is about 120 days. In hemolysis, survival may fall markedly.
Body response to hemolysis
RBC destruction → anemia → reduced oxygen delivery to kidney → increased erythropoietin → bone-marrow erythroid hyperplasia → increased reticulocyte count.
Common consequences:
- Anemia, fatigue, dyspnea
- Reticulocytosis
- Raised unconjugated bilirubin and LDH
- Low haptoglobin
- Jaundice
- Splenomegaly, especially in chronic extravascular hemolysis
- Pigment gallstones in long-standing disease
Two different classifications in your notes
These should not be mixed up.
A. Cause: intracorpuscular versus extracorpuscular
| Type | Meaning | Examples |
|---|---|---|
| Intracorpuscular / intrinsic | Defect lies within the RBC itself | Membrane defects, hemoglobinopathies, G6PD deficiency, pyruvate-kinase deficiency |
| Extracorpuscular / extrinsic | RBC is normal but an outside factor destroys it | Autoimmune hemolysis, microangiopathic hemolysis, infection, burns, prosthetic valves, hypersplenism |
B. Site of destruction: extravascular versus intravascular
| Type | Main location | Main clues |
|---|---|---|
| Extravascular hemolysis | Macrophages in spleen and liver | Jaundice, splenomegaly, spherocytes, raised indirect bilirubin |
| Intravascular hemolysis | Within blood vessels | Markedly low haptoglobin, hemoglobinemia, hemoglobinuria, hemosiderinuria, high LDH |
An intrinsic membrane defect, such as hereditary spherocytosis, generally causes extravascular hemolysis because abnormal RBCs are trapped and removed in the spleen.
3. RBC membrane and membrane skeleton
A normal RBC is a flexible biconcave disc. It must bend repeatedly to pass through narrow capillaries and splenic cords.
The RBC membrane has:
- Lipid bilayer: forms the cell boundary.
- Transmembrane proteins: especially band 3 and glycophorins.
- Membrane skeleton beneath the bilayer: mainly spectrin, ankyrin, actin, protein 4.1, and protein 4.2.
These proteins preserve:
- Shape
- Surface-area-to-volume ratio
- Mechanical stability
- Flexibility and deformability
Important proteins in your list
| Protein | Main function | Defect may cause |
|---|---|---|
| Ankyrin | Links spectrin skeleton to band 3 in membrane | Hereditary spherocytosis |
| Spectrin, alpha or beta | Major flexible cytoskeletal network | Hereditary spherocytosis or hereditary elliptocytosis |
| Band 3 | Anion exchanger and anchor for ankyrin | Hereditary spherocytosis |
| Protein 4.2 | Helps stabilize ankyrin-band 3 linkage | Hereditary spherocytosis |
| Protein 4.1 | Stabilizes spectrin-actin junctions | Hereditary elliptocytosis |
| Actin | Junctional complex and membrane stability | Elliptocytosis-related defects |
| Stomatin | Influences membrane ion transport | Hereditary stomatocytosis |
| Glycophorins | Surface glycoproteins, help membrane organization | Some elliptocytosis variants |
4. Hereditary spherocytosis
This is the major condition emphasized in your final image.
Mechanism
Defects in ankyrin, spectrin, band 3, or protein 4.2 weaken vertical attachments between the membrane skeleton and lipid bilayer.
Membrane loss → reduced surface area relative to cell volume → spherical RBCs called spherocytes.
Spherocytes are less flexible and cannot pass easily through the splenic circulation.
Spherocytes → splenic trapping and macrophage removal → extravascular hemolysis.
Clinical features
- Mild to severe hemolytic anemia
- Jaundice
- Splenomegaly
- Pigment gallstones
- Aplastic crisis after parvovirus B19 infection
- Often autosomal dominant, although recessive forms occur
Investigations
- Spherocytes on peripheral smear
- Reticulocytosis
- High MCHC is a useful clue
- Negative direct antiglobulin test, which helps distinguish it from warm autoimmune hemolytic anemia
- Eosin-5-maleimide binding test is commonly used
- Osmotic fragility may be increased
5. Other inherited membrane disorders
Hereditary elliptocytosis
Usually due to defects involving spectrin, protein 4.1, or glycophorin C.
- RBCs become oval or elliptical rather than round.
- Many patients are asymptomatic.
- Severe forms can cause hemolysis.
Hereditary pyropoikilocytosis
A severe disorder, often related to spectrin abnormalities.
- RBCs are very fragile.
- Marked poikilocytosis and fragmentation can occur.
- Hemolysis may be significant, often presenting in infancy or childhood.
Hereditary stomatocytosis
An abnormal membrane ion permeability disorder.
- RBCs show a slit-like central pallor, called a stoma.
- Water movement changes RBC hydration and shape.
- May cause hemolysis.
Key correction to remember
- Hereditary spherocytosis: primarily loss of membrane surface area due to defective vertical membrane-skeleton attachments.
- Hereditary elliptocytosis: primarily defective horizontal interactions within the cytoskeleton, producing elongated RBCs.
- Both are usually intracorpuscular causes of hemolytic anemia and cause predominantly extravascular hemolysis.
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hereditary spherocytosis AND elliptocytosis
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hereditary spherocytosis elliptocytosis stomatocytosis Merck Manual Professional
These pages explain inherited RBC membrane disorders, which are intrinsic causes of hemolytic anemia.
A normal RBC is a flexible, biconcave disc. Defects in membrane proteins make RBCs lose their normal shape and flexibility. Such cells are trapped and removed by macrophages in the spleen, causing mainly extravascular hemolysis.
1. Hereditary spherocytosis (HS)
What it is
RBCs become spherical rather than biconcave discs.
- On peripheral smear: small, dense spherocytes
- They lack the normal central pallor.
Molecular defect
The usual defects involve proteins that attach the membrane skeleton to the lipid bilayer:
- Ankyrin: most common
- Band 3
- Spectrin: alpha or beta
- Protein 4.2
Your note lists actin, but actin is not among the main classic causes of hereditary spherocytosis.
Mechanism
Membrane-protein defect → membrane instability → repeated loss of membrane fragments → reduced surface area with unchanged cell volume → RBC becomes spherical.
Spherocytes are poorly deformable. They cannot travel easily through splenic cords and are destroyed there:
Spherocytes → splenic sequestration and macrophage destruction → extravascular hemolysis → anemia, jaundice, splenomegaly.
Typical findings
- Anemia of variable severity
- Jaundice from raised unconjugated bilirubin
- Splenomegaly
- Reticulocytosis
- Increased MCHC
- Pigment gallstones in chronic disease
- Direct antiglobulin test, DAT or Coombs test, is negative
The DAT point is important because autoimmune hemolytic anemia can also produce spherocytes, but it usually has a positive DAT. The Merck description of HS confirms that HS is commonly due to defects in spectrin, ankyrin, band 3, or protein 4.2.
Diagnosis
- Peripheral smear
- Eosin-5-maleimide, EMA, binding test: commonly used
- Increased osmotic fragility can support the diagnosis
- Family history and genetic testing when needed
2. Hereditary elliptocytosis (HE)
Also called ovalocytosis in some contexts.
What it is
RBCs are oval, elongated, or cigar-shaped instead of round biconcave discs.
Molecular defect
The usual defects affect horizontal interactions within the RBC cytoskeleton:
- Spectrin, especially alpha-spectrin
- Protein 4.1
- Glycophorin C
Ankyrin is much more strongly associated with hereditary spherocytosis than hereditary elliptocytosis.
Mechanism
Normally, spectrin forms a flexible mesh beneath the cell membrane. In HE, defective spectrin interactions make the membrane skeleton mechanically weak.
Defective membrane-skeleton stability → repeated deformation in circulation → elliptical RBCs.
Clinical features
Most people are:
- Asymptomatic
- Have little or no hemolysis
- Are diagnosed incidentally on a blood smear
Severe disease is uncommon. A severe homozygous form is hereditary pyropoikilocytosis, in which RBCs are very fragile and can show marked hemolysis, fragmentation, and poikilocytosis.
The Merck review of HE notes that hemolysis is usually absent or mild, unlike the more variable hemolysis of HS.
3. Hereditary stomatocytosis
What it is
This is an inherited RBC membrane disorder in which cells show stomatocytes on the smear.
A stomatocyte has a slit-like, mouth-shaped central pallor, not simply a cup shape.
Main problem
This is primarily a disorder of abnormal membrane cation permeability.
There is abnormal movement of:
- Sodium, Na⁺
- Potassium, K⁺
- Water
This changes RBC hydration, shape, and survival.
Types
- Overhydrated hereditary stomatocytosis: RBCs gain sodium and water, swell, and may become macrocytic.
- Dehydrated hereditary stomatocytosis, also called hereditary xerocytosis: RBCs lose water and become dehydrated.
Clinical features
- Variable hemolytic anemia
- Reticulocytosis
- Jaundice
- Splenomegaly may occur
- Stomatocytes on smear, though they may not always be prominent
Important clinical caution: splenectomy is usually avoided in hereditary stomatocytosis/xerocytosis because it can markedly increase thromboembolic risk.
Quick comparison
| Disorder | Main protein/problem | RBC appearance | Hemolysis |
|---|---|---|---|
| Hereditary spherocytosis | Ankyrin, band 3, spectrin, protein 4.2 | Spherocytes, no central pallor | Often clinically significant |
| Hereditary elliptocytosis | Spectrin, protein 4.1, glycophorin C | Elliptocytes, cigar-shaped cells | Usually mild or absent |
| Hereditary stomatocytosis | Abnormal Na⁺/K⁺ permeability and RBC hydration | Stomatocytes, slit-like central pallor | Variable |
One-line memory aid
- Spherocytosis: membrane loss makes the cell round.
- Elliptocytosis: cytoskeletal instability makes the cell oval.
- Stomatocytosis: ion and water imbalance makes the central pallor look like a mouth.
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