Sickle cell disease

1. Sickle cell disease This is an inherited multisystem disorder caused by abnormal properties of RBCs containing HbS. This results from mutation in the β-globin gene that changes the 6th amino acid from glutamic acid to valine

2. Pathophysiology *Hb S arises from a mutation substituting thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG. This causes coding of valine instead of glutamate in position 6 of the Hb beta chain. The resulting Hb has the physical properties of forming polymers under deoxy conditions. It also exhibits changes in solubility and molecular stability. These properties are responsible for the profound clinical expressions of the sickling syndromes.

3. Inheritance--- AR HbS polymerizes reversibly when deoxygenated forming a gelatinous network of fibrous polymers that stiffen RBC membrane, ↑ viscosity, and causes RBC dehydration due to potassium leakage & calcium influx. These changes cause the characteristic sickle shape. They lose their pliability that is needed to pass through the capillaries circulation. Their cell membrane is sticky & adherent to endothelium especially the reticulocytes. This leads to vaso-occlusion & premature RBC destruction (hemolysis). HbS is also unstable & susceptible to oxidant stress.

4. Epidemiology USA prevalence = 8-10% among black newborn. West Africa = 25-30%. USA pregnancy at risk = 4000-5000/year. Africa = 120000/year born with sickle cell disease USA = 50000-60000 living patients.

5. S&S Asymptomatic (sickle cell trait = Hb-AS) Sickle cell disease is seen in homozygous state. Chronic hemolytic anemia, recurrent painful episodes, organ dysfunction (sickle cell disease = Hb-SS)

6. Anemia Hemolytic anemia (most). Mean life span 17 days. Hct= 15-30% + significant reticulocytosis. Most severe in Hb-SS & Hb-Sβ˚thalassemia. Milder in Hb-Sβ+ thalassemia & Hb-SC disease. ---- Low erythropoietin production. Granulocytosis (has significant relation to mortality rate).

7. Painful Crises Acute painful episode is often 1st symptom. Caused by vaso-occlusion. Frequent episodes & frequent hospitalization. Highest frequency in 3rd & 4th decades.

8. Factors ass with freq pain 1. high Hb level 2. α-thalassemia 3. Low Hb F 4. Sleep apnea. This can be ↓ by chronic transfusion therapy.

9. Pptating factors Cold exposure, Dehydration, Infection, Stress, Menses, Alcohol consumption & most of the times Unknown.

10. Site Any area of the body can be affected. Most commonly the back, chest, extremities & abdomen. Duration: few days Severity: varies from mild to agonizing pain. Ass signs: fever, swelling, tenderness, tachypnea, hypertension, nausea & vomiting. Lab. Indicators: ↑ acute phase reactants, ↑ SLDH, IL-1, TNF, & ↑ serum viscosity.

11. Other Crises1) Hemolytic crisis Sudden exacerbation of anemia, ↑ reticulocytosis, & serum bilirubin level. --- ass with coexistent G6PD def

12. 2) Aplastic crisis Transient arrest of erythropoiesis. -- Abrupt ↓ of Hb, reticulocytes count & RBC precursors in BM. -- Duration – a few days. -- Cause – infection e.g. parvovirus B19 -- BM necrosis.

13. 3) Sequestration crisis – in the spleen (sometimes in liver). -- Children < 4 years age, Hb-SC adults, Hb-Sβ+ thalassemia. -- Sudden exacerbation of anemia, reticulocytosis, & tender enlarging spleen (sometimes hypovolemia)

14. 4) Megaloblastic crisis due to folate def because of hemolysis & cell turnover.

15. 5) Hepatic crisis Vaso-occlusion causing ischemia. Other causes of anemia --- renal failure ass.

16. Organ Dysfunction * Auto-splenectomy -- due to repeated splenic infarcts. * Growth retardation – Wt affected more than height. -- Skeletal maturation delayed. -- Retarded sexual maturation in ♂ due to primary hypogonadism, hypopituitarism & hypothalamic insufficiency.

17. * Infection Major cause of morbidity & mortality. -- Strept pnemoniae is most common cause of bacteremia. -- H influenzae type b is the 2nd, affects older children & less fulminant. -- G-ve bacteria e.g. E coli in older pts -- meningitis --S pn, H infl --Bact pneumonia causing acute chest syndrome. -- Osteomyelitis – Salmonella spp.

18. CNS TIA, cerebral infarction, hemorrhage, seizures & coma. -- Cerebral thrombosis 70%.

19. * Pulmonary Acute chest syndrome – dyspnea, chest pain, fever, tachypnea, leucocytosis, radiologic pulmonary infiltrates. -- usually bacterial (sometimes atypical ). -- restrictive lung disease -- pulmonary hypertension

20. * Hepatobiliary -- Gall stones (pigmented) -- Liver dysfunction – vasoocclusion, inf, iron overload -- cirrhosis.

21. * Obst/Gyn Impaired placental blood flow is the major concern -- Spontaneous abortion -- Intrauterine growth retardation & death. -- low birth wt. -- Preeclampsia -- Oral contraceptives are safe & effective

22. * Renal -- Decreased urinary conc ability -- papillary infarct -- RTA -- CRF

23. * Priapism – sustained unwanted painful erection of penis. -- may be recurrent & may lead to impotence

24. * Ocular Retinal artery occlusion, retinal infarct, retinal detachment & hemorrhage.

25. * Bone Avascular necrosis of femoral head, hand & foot, vertebrae & other bones. -- Osteomyelitis. -- arthritis. -- BM necrosis.

26. * Skin – Leg ulcers – ischemic or traumatic, above malleoli & often bilateral. Resistant to healing & recur. -- Myofascial syndrome. * Cardiac – MI in the absence of CAD.

27. Dx CBC – anemia, reticulocytosis, Granulocytosis. Blood film – ISCs RBCs, Howell-Jolly bodies due to asplenia. Sickling test – now only historical. Hb- electrophoresis ---- HbS , HbF, ↓ HbA. Solubility test (Sickledex) – distinguishes HbS which is not soluble. PCR – antenatal Dx SUCB ↑, SLDH ↑, S haptoglobin ↓.

28. ℞ 1) Health care maintenance --- routine clinical visits & lab exam --- Blood bank file. --- Counseling regarding dis, genetics, psychosocial issues. --- Folic acid 1mg/d orally --- TCD noninvasive surveillance of cerebral blood flow to predict impending CVA. --- Retinal evaluation at school age regularly. --- Oral contraception, pelvic exam --- Immunization using conjugated vaccines for S pneumoniae & H influenzae type b every 5 years.

29. 2) Infection ---- outpatient ceftriaxone for febrile children. --- Septicemia needs hospitalization, C&S blood & CSF ---meningitis – cover S pn & H infl for 2 weeks. --- Acute chest synd – Cefuroxime & erythromycin covering Mycop pn & chlamydia. --- Osteomyelitis – anti salmonella antibiotics for 2-6 weeks + surgical drainage or sequestrectomy.

30. 3) Blood Transfusion --- For volume replacement, Aplastic crisis, and to prevent CVA & imminent complications such as acute chest syndrome. ---- Not needed for painful crisis. --- Preop BlT needed. --- Exchange BlT – for emergencies

31. 4) Pain Management Painful crisis – -- Hydration – IV fluid. -- aggressive analgesics e.g. morphine, NSAID. --- Local anesthesia. -- Antidepressant

32. 5) Hydroxyurea --- induce Hb F production --- Ribonucleotide reductase inhibitor --- ↓ painful episodes, acute chest syndrome --- ↓ BlT needed --- improve RBC hydration & deformability, ↓ endothelial sickle cell adherence & PMN count.

33. 6) New ttt --- Clotrimazole, Mg supplements (inhibit Gardos pathway) --- Artificial surfactant e.g. poloxamer 188 --- Nitric oxide acute chest synd & painful episodes. --- Warfarin & mini dose heparin --- Methyl prednisolone pain relief but with rebound --- Valproic acid

34. 7) BMT • 8) Gene therapy