Proliferative sickle cell retinopathy is a high viscosity/high hemoglobin complication that may occur more frequently in HbSC than HbSS, with an incidence of 33% in HbSC.42,104 Spontaneous regression of retinopathy occurs in approximately 32% of eyes, and laser or scatter photocoagulation is an effective intervention.105
• Would the patient need to be transfused prior to splenectomy?
Preoperative transfusion therapy is standard of care for HbSS patients undergoing general anesthesia. The TRAP study found that simple “top off” transfusion to a hemoglobin of 10 g/dL was as effective at preventing postoperative sickle cell–related complications as exchange transfusion to HbS of 30% or less, and had fewer transfusion-related complications like alloimmunization.106 There is little data regarding preoperative transfusions in HbSC disease. A retrospective study suggests that HbSC patients undergoing abdominal surgeries should be transfused.107 The higher hemoglobin level of the typical HbSC patient necessitates exchange transfusion to avoid hyperviscosity.
• Is hydroxyurea therapy indicated in this patient?
• Has it been dosed appropriately?
If the patient had the HbSS subtype, hydroxyurea would be clearly indicated, given his frequent pain events.20 HbSC patients may be placed on hydroxyurea on a case-by-case basis, but evidence for its efficacy in this sickle cell subtype is lacking.108 Large clinical trials like the Multi-Center Study of Hydroxyurea (MSH) that established the safety and efficacy of hydroxyurea in sickle cell anemia excluded HbSC and HbSβ+ patients.109 These mild to moderate subtypes produce less HbF at baseline, and typically have a minimal to modest rise in HbF on hydroxyurea.110 In sickle cell anemia, hydroxyurea is titrated to maximum tolerated dose, defined as an ANC of 2000 to 4000/µL and an ARC of 70,000/µL or higher.53 Because of their lower levels of chronic inflammation and lower reticulocyte counts due to higher hemoglobin levels, many HbSC and HbSβ+ patients have values in that range before initiating hydroxyurea therapy.9 Cytopenias, particularly of platelets in HbSC, occur at low doses of hydroxyurea.111
Of note, although the half-life of hydroxyurea would suggest that 3 times daily dosing is indicated, daily dosing has been found to have equal response and is preferred. Another concern is the monitoring of this myelosuppressive medication. This patient has repeatedly failed to obtain a primary care physician or a hematologist, and hydroxyurea requires laboratory monitoring at least every 2 months, especially in a HbSC patient with a very large spleen who is at significant risk for thrombocytopenia and neutropenia.9
CASE CONTINUED
A week after discharge from his admission for abdominal pain diagnosed as splenic sequestration, the patient presents again to the emergency department with abdominal pain which he reports is his typical sickle cell pain. Hemoglobin is 13.8 g/dL, platelet count is 388,000/µL, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are both 10 times their prior value. Creatinine is 1.2 mg/dL (0.75 mg/dL on his prior admission), and total bilirubin is 3 mg/dL, with 0.3 mg/dL direct bilirubin. He undergoes an ultrasound exam of his gallbladder, which reveals sludge and a possible gallstone. There is no evidence of cholecystitis. General surgery performs a laparoscopic cholecystectomy.
• Was this cholecystectomy necessary?
In patients with sickle cell disease, symptomatic gallstones and gallbladder sludge should be observed; recurrent abdominal pain without a significant change in bilirubin may not be due to gallstones or sludge, and therefore may not be relieved by cholecystectomy.112,113 In sickle cell disease, 40% of patients with gallbladder sludge do not develop gallstones.87 The patient’s bilirubin level was at baseline, and there was no increase in the direct (conjugated) fraction. Watchful waiting would have been appropriate, with cholecystectomy being performed if he experienced recurrent symptoms associated with fatty foods accompanied by an elevation in direct bilirubin.
More concerning and deserving of investigation was his elevated liver enzymes. Patients with sickle cell disease may experience recurrent ischemia and reperfusion injuries in the liver, which is called right upper quadrant syndrome. On autopsy of 70 sickle cell patients, 91% had hepatomegaly and 34% had focal necrosis.114 AST is often elevated in sickle cell disease, as it is affected by hemolysis. In this patient, both AST and ALT are elevated, consistent with a hepatocellular disorder. His abdominal pain and ALT rise may be a sign of a hepatic crisis.115 Rapid resolution of ALT elevation in a matter of days suggests a vaso-occlusive, inflammatory event that is self- limiting. Prolonged AST elevation requires further investigation, with consideration of autoimmune hepatitis, viral hepatitis, or iron overload. Iron overload is unlikely in this patient given his lifetime history of only 1 transfusion. Hepatic iron overload typically occurs in sickle cell disease after a minimum of 10 transfusions.115