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G6PD Deficiency Anaemai

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G6PD

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G6PD Deficiency Anaemai

  1. 1. Glucose-6-phosphate Dehydration Deficiency
  2. 2. Objectives • Introduction • Definition • Factors cause G6PD deficiencyFactors cause G6PD deficiency • Pathophysiology (mechanism) • Symptoms • Lab findings
  3. 3. Hexose monophosphate pathway • Also called pentose phosphate pathway ‘PPP’. • About 5% of glycolysis occurs by this pathway. • In which:
  4. 4. Introduction • FUNCTION OF G6PD • Regenerates NADPH, allowing regeneration of glutathione • Protects against oxidative stress • Lack of G6PD leads to hemolysis during oxidative stress- infection, medication, fava beans • Oxidative stress leads to Heinz body formation, extravascular hemolysis
  5. 5. • Pentose pathway also called the phosphogluconate pathway and the hexose monophosphate shunt is a process that generates NADPH and pentoses (5-carbon sugar) OHHHWW MAAI GAAD!!!! PENTOSE PATHWAY????? (Oxidised form)(Reduced form)
  6. 6. History & Definition • It was discovered in 1950s after it was observed that some black soldiers receiving antimalarial drug primaquine developed hemolytic anemia. • It is the most common red cell enzymopathy associated with hemolysis. • Large no. of abnormal genes code for the
  7. 7. Definition • X-linked disease , sesult in G6PD Deficiency (RBCs enzym deficiency ) asymptomatic unless Oxidative stress causes the RBC’s to break apart. • Inherited –, Recessive
  8. 8. Genetics • The G6PD gene is located on the X chromosome • Thus the deficiency state is a sex-linked trait • Affected males inherit the abnormal gene from their mothers who are usually carriers (heterozygotes)
  9. 9. G6PD Deficiency
  10. 10. G6PD variants • There are over 400 variants of the G6PD enzyme: • G6PD A and G6PD B are the well known variants. G6PD B: The normal G6PD enzyme. G6PD A: found with normal enzyme activity but differ from B by a single amino acid substitution, resulting in a different in electrophoretic mobility.
  11. 11. G6PD variants G6PD A : the common one associated with haemolysis, electrophoretically identical to A but has only 5- 15% of the normal enzymatic activity. Mediterranean G6PD: electrophoretically identical to B but its activity is often 1% less than normal.
  12. 12.   World Health Organization classifies for G6PD genetic variants • Class I: Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia • Class II: Severe deficiency (<10% activity), with intermittent hemolysis • Class III: Mild deficiency (10-60% activity), hemolysis with stressors only
  13. 13. • Class IV: Non-deficient variant, no clinical sequelae • Class V: Increased enzyme activity, no clinical sequelae   World Health Organization classifies for G6PD genetic variants
  14. 14. • Individuals who have inherited one of the many G6PD mutations do not show clinical manifestation. • Some of patients with G6PD develop hemolytic anemia if they are exposed or ingest any of the followings oxidizing agents: 1-1-Oxidant drugsOxidant drugs: Remember “AAA”? AntibioticsAntibiotics : e.g. sulfamethoxazole AntimalariasAntimalarias : e.g. primaquine AntipyreticsAntipyretics : e.g. acetanilid 2-2- Favism:Favism: The hemolytic effect of ingesting of fava beans is not observed in all individuals with G6PD deficiency but all patients with favism have G6PD deficiency factors cause G6PD deficiency:factors cause G6PD deficiency:
  15. 15. G6PD Deficiency • Biochemistry – summary • G6PD Reduces • NADP+ • to • NADPH Which is responsible for • Glutathione Which fights • Free radicals Which damage blood cells
  16. 16. Pathophysiology • Oxidative denaturation of hemoglobin is the major cause of H. A in G6PD deficiency • It is important in the conversion of glucose-6- P to phosphogluconate • For subsequent production of NADPH & reduced glutathione (GSH) • GSH protects enzymes & hemoglobin against oxidation by reducing H2O2 & free radicals
  17. 17. Pathophysiology • H2O2 is generated normally in small amounts during normal red cell metabolism • Larger amounts produced when an oxidant drug interacts with oxyhemoglobin • Normal red cells have sufficient G6PD activity to maintain adequate GSH levels • When deficient, red cells fail to produces sufficient G6PD to detoxify peroxide
  18. 18. Pathophysiology • Hb is then oxidized to Hi, heme is liberated from globin & globin denatures producing Heinz bodies • Heinz bodies attach to membrane sulfhydryl groups inducing cell rigidity • At this point red cells can no longer traverse the splenic microcirculation • Hence lysis occurs
  19. 19. Symptoms • Persons with this condition do not display any signs of the disease until their red blood cells are exposed to certain chemicals in food or medicine, or to stress. • Symptoms are more common in men and may include: • Dark urine • Enlarged spleen • Fatigue • Pallor • Rapid heart rate • Shortness of breath • Yellow skin color (jaundice)
  20. 20. G6PD Deficiency • Malaria Treatment – chloroquine – atovaquone-proguanil (Malarone®) – artemether-lumefantrine (Coartem®) – mefloquine (Lariam®) – quinine – quinidine – doxycycline (used in combination with quinine) – clindamycin (used in combination with quinine) – primaquine
  21. 21. Diagnosis ofDiagnosis of G6PD Deficiency Hemolytic AnemiaG6PD Deficiency Hemolytic Anemia 1-CBC Bite cells, blister cells, irregular small cells, Heinz bodies, polychromasia G-6-PD level Bite” cells Spleen removes portion of RBC that had Heinz body, preventing intravascular hemolysis • 2-Screening: • Qualitative assessment of G6PD enzymatic activity (UV-based test)
  22. 22. Diagnosis ofDiagnosis of G6PD Deficiency Hemolytic AnemiaG6PD Deficiency Hemolytic Anemia • 3-Confirmatory test: • Quantitative measurement of G6PD enzymatic activity 4-Molecular test: • Detection of G6PD gene mutation
  23. 23. Special test • Methemoglobin reduction test
  24. 24. Methemoglobin Reduction Test • Sodium nitrite converts Hb (hemoglobin) to Hi (methemoglobin) • Adding methylene blue should stimulate the pentose phosphate pathway, reducing methemoglobin • In G6PD Deficiency, methemoglobin persists
  25. 25. Methemoglobin Reduction Test • Normal blood → clear red color • Deficient blood → brown color • Deficient blood Normal blood
  26. 26. Clinical Manifestations • The patient may experience an acute hemolytic crisis within hours of exposure to the oxidant stress • Hemolytic crisis is self-limited even if the exposure continues & • Only older cell population is rapidly destroyed • A minority of patients are sensitive to exposure to fava beans (favism phenomenon)
  27. 27. What is PNH? • Paroxysmal – sudden onset • Nocturnal – occuring at night (or early in morning upon awakeneing) • Hemoglobinuria Despite the name, most patients do not present this way.
  28. 28. What is PNH? • A rare and unusual acquired hematologic disorder characterized by – Intravascular hemolysis – Bone marrow failure (cytopenias) – Thrombosis.
  29. 29. What is PNH? • Intravascular RBCs break down result from Complement activation due to absence of CD55, CD59 SymptomsSymptoms - passage of dark brown urine in the- passage of dark brown urine in the morningmorning..
  30. 30. . PNH –laboratory features:. PNH –laboratory features: - pancytopenia- pancytopenia - chronic urinary iron loss- chronic urinary iron loss - serum iron concentration decreased- serum iron concentration decreased - hemoglobinuria- hemoglobinuria - hemosiderinuria- hemosiderinuria -- positive Ham’s test (acid hemolysis test)positive Ham’s test (acid hemolysis test) - positive sugar-water test- positive sugar-water test - specific immunophenotype of erytrocytes- specific immunophenotype of erytrocytes (CD59, CD55)(CD59, CD55)

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