Diagnosis

Sickle cell disease

Etiology

Cause [sma]

• A genetic autosomal recessive disorder caused by mutation of hemoglobin and occurs in children of carriers who inherit the sickle cell gene from both parents (homozygote HbSS) or double heterozygote for HbS and b-0 thalassemia

Pathophysiology [sma]

1. Under deoxy conditions, HbS have decreased solubility (coagulopathy), decreased molecular stability, increased viscosity, and polymerization forming a gel-like substance containing Hb crystals called tactoids

2. If oxygen is present, the liquid state prevails

3. Vaso-occlusive crises are often precipitated by cold weather (vasospasm), hypoxia, infection, dehydration, acidosis, alcohol intoxication, emotional stress and pregnancy

4. In addition, RBC lifespan is greatly shortened (10-20 days)

5. Clinical manifestation

   1. Hemolytic anemia --> Hepatosplenomegaly

   2. Vaso-occlusive crisis --> Multiple organ damage from microinfarcts:

      • Heart

      • Skeleton

      • Central nervous system

      • Spleen

      • Kidney

   3. Immune deficiency and severe infections with encapsulated organisms such as Haemophilus influenzae, Streptococcus pneumoniae: pneumonia, osteomyelitis

   4. Acute Chest Syndrome (pulmonary embolism, fluid overload, infection): cough, dyspnea, fever

   5. Stroke: headache, altered mental status, slurred speech, seizures, and paralysis

   6. Aplastic crises from Parvovirus B-19: Fatigue, anemia, dyspnea, and even syncope

   7. Acute intrahepatic cholestasis: RUQ pain, jaundice, hepatomegaly and liver failure

   8. Priapism

   9. Acute Ocular Complications: Hyphema, retinal artery occlusion, orbital infarction, Orbital Compression Syndrome

   10. Chronic Complications:

       • Avascular Necrosis of Joints

       • Leg ulcers

       • Pulmonary Artery Hypertension

       • Iron overload

Risk factors [sma]

• Subsaharan Africa: Heterozygotes who carry one HbS allele have some resistance to malaria caused by Plasmodium falciparum, thus more prevalent in endemic areas

Complications [sma]

• Acute vaso-occlusive crisis:

  1. Acute chest syndrome

  2. Sequestration crises: splenic or hepatic sequestration

  3. Fat embolism

  4. Bone infarction/necrosis

  5. Coagulopathy: stroke, myocardial infarction, venous thrombosis

  6. Ophthalmic: vitreous hemorrhage, retinal detachment, retinal artery/vein occlusion

  7. Aplastic crises

  8. Papillary necrosis

• Chronic Complications

  1. Delayed growth and development and growth retardation

  2. Cardiac: cardiomegaly, cardiomyopathy, left ventricular hypertrophy, arrhythmia, congestive heart failure

  3. Pulmonary: pulmonary edema, sickle cell lung disease, pulmonary hypertension

  4. Hepatobiliary: hepatomegaly, intrahepatic cholestasis, cholelithiasis, viral hepatitis

  5. Splenic complications: splenomegaly, hyposplenia, asplenia

  6. Renal: acute and chronic renal failure, pyelonephritis, renal medullary carcinoma

  7. Musculoskeletal: degenerative changes, osteomyelitis, septic arthritis, osteonecrosis, osteopenia/osteoporosis

  8. Neurologic: aneurysm, mental retardation

  9. Ophthalmic: proliferative sickle retinopathy, vitreous hemorrhage, retinal detachment, nonproliferative retinal changes

  10. Endocrine: primary hypogonadism, hypopituitarism, hypothalamic insufficiency

  11. Iron overload due to repeated transfusions

Epidemiology

Incidence per 100.000 [sma][tq6][qot][u39][two]

Approach

• Blood test: CBC with differential and reticulocyte count, electrolytes, creatinine, BUN, ALAT, bilirubin, secretory phospholipase A2 (sPLA2) [u39]

• Blood gas

• Blood culture

• Urinanalysis

• Blood smear

• Electrophoresis: presence of homozygous hemoglobin S (HbS)

• Lumbar puncture: CSF analysis

• Chest x-ray

• CT femur

• Nuclear medicine scanning: osteonecrosis

• MRI

• Abdominal ultrasonography

• Echocardiography

• Transcranial near-infrared spectroscopy or cerebral oximetry: screen for low cerebral venous oxygen saturation in children with SCD

Treatment

1. Blood transfusion and Erythrocytapheresis: [sma][u39]

   • Pregnant females if Hb > 7 gm/dL

   • Preoperative transfusion for medium-risk surgery

   • Symptomatic patients as listed below

2. Vaso-occlusive crises: Cold weather (vasospasm), hypoxia, infection, dehydration, acidosis, alcohol, emotional stress, pregnancy

   • Vigorous intravenous hydration

   • Analgesics: NSAIDs, opioids

   • Supplemental oxygen

3. Acute Chest Syndrome: (Fat embolism, Infections, Asthma)

   • Antibiotics, including coverage for atypical bacteria

   • Supplemental oxygen

   • Blood transfusion is recommended for hypoxic patients

   • Respiratory system: beta-adrenergic dilators (if asthma), incentive spirometry

   • Prophylaxis: Disease-modifying therapy (hydroxyurea) or chronic blood transfusion program

4. Sequestration Crises: sequestered blood --> hepatosplenomegaly

   • IV fluids, pain control, and simple/exchange blood transfusion

   • Splenectomy if life-threatening or recurrent splenic sequestration or hypersplenism

5. Acute Stroke:

   • Acute and prophylactic simple or exchange blood transfusion

   • Disease-modifying therapy

6. Aplastic Crises (parvovirus infection, folic acid deficiency, bone marrow toxins):

   • Exchange/simple transfusion

7. Infections: Oral or intravenous antibiotics

8. Priapism:

   • Conservative measures: Analgesics, hydration, and sedation

   • Penile aspiration or irrigation of corpora cavernosa with alpha-adrenergic drugs

9. Acute ocular Complications:

   • Hyphema: Anterior chamber paracentesis or surgical intervention

   • Reducing intraocular pressure

   • Infections: antibiotics

   • OCS: Corticosteroids to relieve excessive pressure

10. Avascular Necrosis: Pain management, physical therapy and hip arthroplasty

11. Leg Ulcer: wound care, wet-to-dry dressings, pain control, antibiotics (osteomyelitis)

12. Pulmonary Hypertension: Referred to pulmonologists for management

13. Renal Complications: albuminuria, ACE-inhibitor, kidney transplantation

14. Ophthalmologic Complications:

    • Laser photocoagulation therapy to manage proliferative sickle retinopathy

    • Vitrectomy or retinal repair if vitreal hemorrhage or retinal detachment

15. Iron Overload: good transfusion practices

    • Transfusion restricted to the management of symptoms

    • Exchange transfusion over simple transfusion

    • Iron chelation therapy (if serum ferritin > 1000 mcg/L, LIC >7mg Fe/gm dry weight)

      • Deferasirox: 10-20mg/kg/day

      • Deferoxamine injection 1 to 2 g/day (SC) or 40-50 mg/kg/day (IV)

      • Deferiprone

16. Hematopoietic Stem Cell Transplant: A potentially curative option

Differential diagnoses

Anemia, Aortic arch syndrome, Aortic regurgitation, Aortic stenosis, Babesiosis, Blood transfusion, Carotid cavernous fistula, Cholelithiasis, Clostridium difficile, Drug side effects, Glucose-6-phosphate dehydrogenase deficiency, Heart failure, Hemoglobinopathy, Hemolytic anemia, Hemolytic uremic syndrome, Henoch-Schönlein purpura, Hereditary spherocytosis, Incontinentia pigmenti, Legg-Calve-Perthes disease, Leukemia, Macroglobulinemia, Malaria, Microscopic polyangiitis, Mitral regurgitation, Mitral stenosis, Muscular dystrophy, Myocardial infarction, Osteomyelitis, Paroxysmal nocturnal hemoglobinuria, Pneumonia, Polycythemia vera, Priapism, Pulmonary embolism, Pulmonary hypertension, Pyruvate kinase deficiency, Retinopathy, Rheumatoid arthritis, Rickettsia, Sepsis, Septic arthritis, Stroke, Systemic lupus erythematosus, Thalassemia, Thrombotic thrombocytopenic purpura, Tricuspid stenosis, Uveitis, Wegener's granulomatosis