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Hereditary Spherocytosis

Hereditary Spherocytosis: Pathogenesis and clinical findings Gene mutation of SLC4A1 (Band 3: Transmembrane anchor protein) Gene mutation of ANK1 (Ankyrin-1: Adaptor protein binding a & b Spectrin to cell membrane) Gene mutation of SPTB (b Spectrin: Scaffold protein) Gene mutation of SPTA1 (a Spectrin: Scaffold protein) Gene mutation of EPB42 (Protein 4.2: Band 3 & Ankyrin linker protein) Authors: Catherine R Jarvis Reviewers: Sergio Sharif, Yan Yu*, Kareem Jamani* * MD at time of publication Mutation is inherited via autosomal dominant pattern (inherits 1 copy from an affected parent) Mutation is inherited via autosomal recessive pattern (inherits 1 copy from both affected or carrier parents) Gene mutation limits adequate production of associated RBC (red blood cell) structural protein Structural protein deficiency hinders RBC from maintaining good adherence between outer bilipid cell membrane & spectrin cytoskeleton (inner scaffolding) ↓ RBC membrane stability results in cell losing portions of its cell membrane in circulation à ↓ RBC surface area in relation to its volume Normally discoid-shaped RBCs become non-flexible, smaller than usual spherically shaped cells (spherocytes) Hereditary Spherocytosis Rigid spherocytes cannot adequately deform to pass through spleen microcirculation for clearance (removal) Splenic red pulp macrophages phagocytose & intracellularly hemolyze (breakdown) trapped spherocytes Hemolyzed spherocytes release hemoglobin inside macrophages ↓ Circulating number of RBCs Spleen cannot clear spherocytes with sufficient speed Routine cellular processes convert the heme group inside hemoglobin molecules into bilirubin, which is then released into circulation Hemolytic anemia (↓ hemoglobin from hemolysis) Spherocyte overload physically expands size of spleen Splenomegaly (enlarged spleen) ↓ ability to carry O2 (oxygen) in circulation Liver normally conjugates bilirubin for excretion. ↑ Bilirubin levels in circulation overwhelm the liver’s ability to conjugate all available bilirubin molecules Kidneys sense ↓ O2 Kidneys release erythropoietin (EPO) ↑ Unconjugated bilirubin in circulation ↑ Unconjugated bilirubin in bile Bilirubin deposits in skin & eyes EPO stimulates bone marrow to ↑ reticulocytes Jaundice (yellow skin & eyes) Cholelithiasis (gallstones)** Reticulocytosis (>2.5%) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Body cannot efficiently carry out cellular respiration Fatigue Body restricts blood flow to less critical areas like skin Pallor (pale skin) Chemoreceptors detecting low oxygen trigger sympathetic nervous system Tachycardia (fast heart rate) Tachypnea (fast breathing rate) **See corresponding Calgary Guide slide(s) Published Dec 17, 2025 on www.thecalgaryguide.com