Sickle cell disease sandip

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Sickle cell disease sandip

  1. 1. DR SANDIP GUPTA PGT, PEDIATRICS
  2. 2. Prevalence/Incidence of SCD  In African-Americans the incidence of SCD is 1 in 375 for HbSS, 1 in 835 for HbSC and 1 in 1,667 for Sickle beta-thalassemia. In addition, 1 in 12 African-Americans are carriers for the disorder  In other U.S. populations, the prevalence of sickle cell disease is 1 in 58,000 Caucasians; 1 in 1,100 Hispanics (eastern states); 1 in 32,000 Hispanics (western states); 1 in 11,500 Asians; and 1 in 2,700 Native Americans
  3. 3. Sickle Cell Disorders in India
  4. 4. What Is Sickle Cell Disease?  An inherited disease of red blood cells  Affects hemoglobin  Polymerization of hemoglobin leads to a cascade of effects decreasing blood flow  Tissue hypoxia causes acute and chronic damage β-globin gene (chromosome 11q) mutation GAGGTG at 6th codon Glutamic Acid  Valine at the 6th amino acid along the β-globin chain
  5. 5. Why Do Cells Sickle? Sickling Mechanism 1. Deoxygenation HgbS  protein conformational change 2. Hydrophobic Valine exposed at molecular surface 3. Val6 of B2 chain of 1st Hgb S chain forms hydrophobic bond with Phe85 and Leu88 of a 2nd Hgb S B1 chain 4. Pairing Hgb S monomers polymerize to form Hgb S chains 5. Hgb S polymers precipitate in RBCs as long, rigid fibers.
  6. 6. Pathophysiology  HgbS fibers are rigid  Hgb S fibers deform RBC membranes  Membrane disruption exposes transmembrane proteins and lipids that are pro-inflammatory  Progressive sickling makes cells dense and inflexible Frenette et al., Journal of Clinical Investigation 117(4): 850-858, 2007
  7. 7. Pathophysiology Factors that Promote Hgb S polymerization: Low pO2 / Hypoxia Prolonged “Delay Time” – time RBC spends in microcirculation Low pH High Hgb S concentration Genotype-dependent Cellular “Dehydration” Volume depletion (total body) Sickling  Activation K+ / Cl- cotransporter and Gardos Ca2+- activated K+ efflux channels  ion and water efflux Low Hgb F concentration  α2γS: gamma globin chains bind Hgb S chains and inhibit Hgb S polymerization, thus countering sickling process
  8. 8. Normal Vs. Sickle Red Cells Normal  Disc-Shaped  Deformable  Life span of 120 days Sickle  Sickle-Shaped  Rigid  Lives for 20 days or less
  9. 9. Clinical Syndromes Disease Severity is Genotype –Dependent Genotype Hgb SS Hgb S / β0 thalassemia Hgb SC Hgb S / α thalassemia Hgb S / D Hgb S / A Hgb S / E Hgb S / β+ thalassemia Hgb S / HPFH WorseningDiseaseSeverity Asymptomatic + / - Mild Anemia
  10. 10. Interpreting Newborn Screening Results Sickle Hemoglobinopathies Screening Results* Associated Disorder FS SS or Sβ°thalassemia FSC SC FSA S ß+ thalassemia FSE S Hemoglobin E FS Variant S Variant FAS Sickle Cell Trait FAC Hb C Carrier FAE Hb E Carrier FA Variant Hb Variant Carrier onfirmation.
  11. 11. Hemolysis and Vaso-occlusion Vaso-occlusion: Occurs when the rigid sickle shaped cells fail to move through the small blood vessels, blocking local blood flow to a microscopic region of tissue. Amplified many times, these episodes produce tissue hypoxia. The result is pain, and often damage to organs. Hemolysis: The anemia in SCD is caused by red cell destruction, or hemolysis, and the degree of anemia varies widely between patients. The production of red cells by the bone marrow increases dramatically, but is unable to keep pace with the destruction.
  12. 12. Chronic Manifestations:  Anemia  Jaundice  Splenomegaly  Functional asplenia  Cardiomegaly and functional murmurs  Hyposthenuria and enuresis  Proteinemia  Cholelithiasis  Delayed growth and sexual maturation  Restrictive lung disease*  Pulmonary Hypertension*  Avascular necrosis  Proliferative retinopathy  Leg ulcers  Transfusional hemosiderosis* Acute Manifestations:  Bacterial Sepsis or meningitis*  Recurrent vaso-occlusive pain (dactylitis, muscoskeletal or abdominal pain)  Splenic Sequestration*  Aplastic Crisis*  Acute Chest Syndrome*  Stroke*  Priapism  Hematuria, including papillary necrosis Hemolysis and Vaso-occlusion (continued) *Potential cause of mortality
  13. 13. Fever and Infection  Fever > 38.5° C (101°F) is an EMERGENCY  Basic laboratory evaluation:  CBC with differential and reticulocyte count, blood, urine, and throat cultures, urinalysis, chest x-ray  Indications for hospitalization & IV antibiotics: -Child appears ill -Any temperature > 40°C -Abnormal laboratory values  Start IV antibiotics IMMEDIATELY if child appears ill or temperature > 40°C (DO NOT WAIT FOR LABS)
  14. 14. Acute Chest Syndrome Clinically: Acute onset of fever, respiratory distress, chest pain, new infiltrate on chest x-ray. Causes  Infection  Fat emboli  Lung infarct Since you cannot distinguish between acute chest syndrome and pneumonia clinically there is no change in treatment. A leading cause of death in sickle cell disease
  15. 15. ACS : Treatment  Oxygen ( Spo2>90%)  Blood transfusion therapy  Emperical antibiotics( cephalosporin+ macrolides)  Cont respiratory therapy( incentive spirometry,physio)  Optimum pain control  Fluid management.
  16. 16. Priapism: INVOLUNTARY ERECTION FOR>30 min STUTTERING&REFRACTORY Treatment is difficult  Opioid pain medication  Intravenous fluids  Aspiration and irrigation of the corpus cavernosum(>4hr)  Blood Transfusions  Impotence with severe disease or recurrent episodes  Prevention: Hydroxyurea,Etilefrine  Surgical shunt procedures Urethr a Corpus cavernosum Commonly occurs in children and adolescents with SS or SC Age of onset is 5-35 yrs. Early morning
  17. 17. Stroke: Any focal neuro deficit>24hr&/or↑intT2W MRI  Historically 8 to 10% of children with SS  “Silent Stroke” in 22% of children with hemoglobin SS Any acute neurologic symptom other than mild headache, even if transient, requires urgent evaluation. Treatment: Chronic transfusion therapy to maintain sickle hemoglobin at or below 30%
  18. 18. Splenic Sequestration  Sudden trapping of blood within the spleen  Usually occurs in infants under 2 years of age with SS  Spleen enlarged ,hypovolemia, Hb↓>2% ,reticulocytosis ,↓pl atelet count,may not be associated with fever, pain, respiratory, or other symptoms  Circulatory collapse and death can occur in less than thirty minutes •Recurrence very common (50%) •Associated with high mortality (20%)
  19. 19. Splenic Sequestration  Hemoglobin SS  Incidence increased: 6 and 36 months  Overall incidence about 30%  Hemoglobin SC  Incidence increased: 2 and 17 years  Mean age 8.9 years  Can occur in adolescence and adulthood  Incidence about 5%
  20. 20. Treatments For Splenic Sequestion  Intravenous fluids  Maintain vascular volume  Cautious blood transfusion  Treat anemia with 5ml/kg of PRBC  splenectomy  If indicated
  21. 21. Pain Management Acute pain  Hand-foot syndrome (dactylitis)  Painful episodes: vasoocculsion  Splenic sequestration  Acute chest syndrome  Cholelithiasis  Priapism  Avascular necrosis  Right upper quadrant syndrome
  22. 22. PRECIPTATING FACTORS: physical stress, infection , dehydration,hypoxia ,exposure to cold, acidosis Pain is an emergency Hospital evaluation:  Hydration: 1.5 times maintenance unless acute chest syndrome suspected  Assess pain level and treat  Do not withhold opioids  Frequently reassess pain control  Assess for cause of pain/complications
  23. 23. Pain Management Mild-moderate pain  Acetaminophen  Hepatotoxic  Non-steroidal anti-inflammatory agents (NSAIDs) -Contraindicated in patients with gastritis/ulcers and renal failure -Monitor renal function if used chronically
  24. 24. Pain Management  Moderate-severe pain  Opioids are first-line treatment  Morphine sulfate or hydromorphone  Meperidine NOT recommended  (Metabolite causes seizures & renal toxicity)  Moderate or less severe pain  Acetaminophen or NSAID's in combination with opioids  Other adjuvant medications (sedatives, anxiolytics)  May increase efficacy of analgesics
  25. 25. Hand Foot Syndrome - Dactylitis  Early complication of sickle cell disease  Highest incidence 6 months to 2 years  Painful swelling of hands and feet  Treatment involves fluids and pain medication  Fevers treated as medical emergency
  26. 26. Renal Disease  Renal findings  Decreased ability to concentrate urine  Decreased ability to excrete potassium  Inability to lower urine pH normally  Hematuria / papillary necrosis  Risk factors for progressive renal failure  Anemia, proteinuria, hematuria
  27. 27. Gall Bladder and Liver  Gall stones and biliary sludge  Monitor by ultrasound every 1-2 years  Cholestasis  May progress, leading to bleeding disorders or liver failure  Iron overload  Due to chronic transfusions  Chronic hepatitis
  28. 28. Bone Disease Diagnosis and Treatment  Avascular necrosis of hips and shoulders  Index of suspicion  Persistent hip or shoulder pain  Plain film or MRI  Treatment  Conservative  NSAID’s and 6 weeks of rest off affected limb  Physical therapy
  29. 29. Chronic Complications  Anemia/Jaundice  Brain Damage/Stroke  Kidney failure  Decreased lung function  Eye disease (bleeding, retinal detachment)  Leg ulcers  Chronic pain management
  30. 30. GENETIC COUNSELLING  Who should receive counseling? -Parents of newborns with sickle disorders or traits -Pregnant women/ prenatal counseling  What is the purpose of counseling? -Education -Informed decision-making  Content should include: -Genetic basis, chances of disease or trait (potential pregnancy outcome), disease-related health problems, variability/unpredictability of disease, family planning, average life span
  31. 31. Health Maintenance Frequent visits: every 3 to 6 months  Immunizations  Routine immunizations  Hib- 6 months and older  23 valent Pneumovax at five years  Penicillin prophylaxis beginning no later than two months  Nutrition and fluids  Folate supplementation is controversial
  32. 32. Health Maintenance  Physical exam with attention to:  Growth and development, jaundice, liver/spleen size, heart murmur of anemia, malocclusion from increased bone marrow activity, delayed puberty  Lab evaluations:  CBC with differential and reticulocyte count, urinalysis, renal & liver function
  33. 33. Health Maintenance Special studies  Brain- Transcranial doppler ultrasonography, MRI/MRA  Lungs- Pulmonary function tests, Echo cardiogram for pulmonary hypertension  Neurologic- neuropsychological testing
  34. 34. Current Recommendations  Penicillin Prophylaxis: SS, S ºThalassemia  2 months to 3 years: 125 mg PO BID  Over 3 years: 250 mg PO BID  When to discontinue is controversial  Penicillin Prophylaxis: SC and S + Thalassemia  SC warrants penicillin prophylaxis similar to SS  S + Thalassemia: penicillin prophylaxis can be safely discontinued at 5 years  Routine use in infants and children is controversial  Special Circumstances  History of repeated sepsis, surgical splenectomy
  35. 35. Therapy Hydroxyurea S-phase cytotoxic, myelosuppressive drug: inhibits ribonucleotide reductase Induces proliferation of early erythroid progenitors Leads to ↑ Hgb F production (α2γ2) γ subunit production  α2 γS  does not polymerize Additional effects of hydroxyurea: ↓ Neutrophil numbers and neutrophil activation ↓ stress reticulocytes, ↓ reticulocyte adhesion ↓ endothelial adhesion properties (↓VCAM-1, ↓ laminin, ↓thrombospondin) Improved RBC hydration and MCV Increased [Hgb]
  36. 36. Therapy Hydroxyurea Dosing:  Initiation of Treatment: Hydroxyurea 15-20mg/kg/day in single daily dose Check CBC Q 2wks, Hgb F Q 6-8 wks, serum chem Q 2-4 wks May require Tx Continuation: If no major toxicity, escalate dose Q 6-8wk by 2.5-5 mg/kg until desired endpoint reached may go upto 35mg/kg Reduces painful episodes, ACS by 50%. Treatment Endpoints: Decreased pain / pain crises Hgb F 15-20% Acceptable myelotoxicity: <2500 neutrophils / ul < 90,000 platelets / ul Hgb < 5.3 g/dL
  37. 37. Therapy Other Hgb F – inducing Agents  Short-chain fatty acids (sodium butyrate) Mechanism: Histone deacetylation Baboons: ↑ Hgb F Phase II study (N=15): 11 responders, Increased Hgb F 7% 21%  5-Azacytidine and 5-Aza-2’deoxycytidine Mechanism: Demethylation of DNA 9-month Phase I/II study (N=7): Increased Hgb F 3.1%  13.9% Erythropoietin
  38. 38. Therapy Allogeneic Stem Cell Transplantation Only Therapy Offering Curative Potential for sickle cell disease As of 2002, only ~150 patients had undergone SCT Patient recruitment hindered by: Difficult pt selection - Absence of early prognostic markers in SCD Majority of patients do not have donor High mortality risk of SCT Risk of long-term treatment-induced malignancy Risk of GVHD Pts >16 have demonstrated poor outcomes d/t comorbidities Two multicentre series of allogeneic SCTs have been undertaken, 1 in US, 1 in Europe
  39. 39. 2002 NIH Guidelines for SCT Eligibility in Sickle Cell Disease
  40. 40. Therapy Gene Therapy  Goal: Transfer anti-sickling β-globin genes  Obstacles:  poor onco-retroviral vector stability  low viral titres and gene transfer efficiency  difficulty packaging large β-globin gene and regulatory elements  safety concerns
  41. 41. THANK YOU

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