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Chronic organ injuries in SCD children
SCI are the most common neurological events in SCD children, occurring in approximately one-third of patients before the age of 14 years; there is no plateau with increasing age.83 Reported risk factors for SCI include male gender, lower baseline hemoglobin concentrations, higher baseline systolic blood pressure, and previous seizures.78
Screening and prevention
The brain is probably the only organ for which preven- tive strategies have shown efficacy in SCD patients. Transcranial Doppler (TCD) measures the flow velocity in the large intracranial arteries of the circle of Willis where stenosis or flow turbulences may induce a local acceleration. Children may be stratified as being at low, intermediate, or high risk of stroke according to normal, conditional, or abnormal velocities, respectively.9 Adams et al. showed that children with time-averaged mean velocity (TAMV) measured in the distal internal carotid artery or middle cerebral artery ≥200 cm/s had a 6-fold higher risk of stroke than children with normal TCD velocities (TAMV <170 cm/s).9 For these high-risk patients, initiation of monthly blood transfusion reduced the risk of stroke by 90%.84 Alternatively, hydroxyurea has been used for primary and secondary stroke preven- tion in low-resource settings.85 Cerebral vasculopathy revealed by abnormal TCD is an indication for hematopoietic stem cell transplant in children with HLA- identical sibling. When velocities are normal, the current recommendation in children with HbSS and HbS/b0-tha- lassemia is annual TCD screening from 2 to ≥16 years.37 Conditional TCD is an intermediate category that war- rants performing MRI/magnetic resonance angiography (MRA) and controlling TCD, as conversion to abnormal TCD may occur.86 Many teams consider conditional velocities as an indication for hydroxyurea treatment.38 Very low blood-flow velocities (<70 cm/s) suggest post- stenotic demodulation or near-occlusive arterial disease.87 Finally, elevated velocities (>160 cm/s) in the extracranial part of the internal carotid artery are also associated with increased risk of stroke, notably in patients who are free of intracranial arterial vasculopathy;88,89 however, there is still no clear recommendation on which treatment strate- gy to use. Our personal recommendation is to use the same strategy for both intra- and extra-cranial abnormal- ities. TCD may detect blood flow alterations before occurrence of MRI/MRA abnormalities allowing for early management at a stage when it might be possible to pre- vent the situation worsening.90 MRI/MRA is recommend- ed in children with conditional TCD findings and in chil- dren with incomplete TCD assessment, usually due to a lack of a bone window or to an underlying arterial occlu- sion. In 2014, a panel of experts did not recommend sys- tematic MRI in asymptomatic children with HbSS and HbS/b0-thalassemia.37 However, brain MRI can reveal aneurysms or SCI, which are associated with decreased cognitive ability, and these might benefit from hydrox- yurea treatment. Therefore, some centers recommend performing brain MRI in SCD children at least once.91 Our personal experience is to recommend systematic MRI at around six years of age (an age at which it is expected that most children would have already started school) since early diagnosis of SCI usually leads to a more thor- ough evaluation of academic ability and performance with implementation of educational and psychological
support when required. Management of SCI is still non- consensual. Hydroxyurea has been suggested to reduce their extension or recurrence.92 Use of chronic transfusion is a subject of debate as this therapy has only moderate efficacy on the progression of SCI.91
Liver disease
The main acute manifestations of liver disease in SCD include sickle cell hepatic crisis, sickle cell intrahepatic cholestasis, and hepatic sequestration, while chronic manifestations include cholelithiasis, sickle cell cholan- giopathy, auto-immune hepatitis, viral hepatitis, and iron overload.93 The prevalence of liver disease in adults with SCD is estimated to be approximately 10%.93 In a cohort of 3,500 adult patients, liver failure was considered to be the cause of death in 7% of cases.8 Hepatobiliary compli- cations are more rarely reported in children with SCD, most probably because they are not routinely screened for and are thus under-diagnosed.94
The pathophysiology of these complications is mostly related to the sickling of red blood cells, resulting in sinu- soidal obstruction and ischemia of hepatocytes, as well as ischemia of bile ducts leading to cholangiopathy. Hemolysis-related hyperbilirubinemia promotes biliary lithiasis. Liver damage in SCD may also be due to iron overload, viral infection, or autoimmune disorders, the frequency of which is increased in SCD patients com- pared to the general population.95
A retrospective review of 616 SCD children followed- up in a reference center for both SCD and hepatology found that 37% had presented at least one hepatobiliary complication.94 Among chronic complications, gallstones were diagnosed in 25% of children, cholangiopathy in 0.8%, autoimmune hepatitis in 0.5%, transfusion iron overload in 3%, and iron chelator toxicity was suspected in 0.8%. Over half of the gallstones were discovered inci- dentally, although complications occurred in 42% of cases, mostly occurring as pain, as well as cholecystitis, cholangitis, and pancreatitis. Among acute complications, the combined prevalence of acute sickle cell crisis, sickle cell intrahepatic cholestasis, and acute hepatic sequestra- tion was approximately 6%.94 Post-transfusion iron over- load is usually asymptomatic in children but may have severe consequences in adults.93
Screening and prevention
In order to prevent gallstone-related complications, we recommend abdominal ultrasonography once a year after the age of five years, and elective cholecystectomy in case of gallstone even in asymptomatic patients, although there is currently no consensus for this preventive strate- gy.37,96 Liver injury can be screened by performing twice- yearly liver tests (mainly alanine aminotransferase [ALT] and conjugated bilirubin).94 In patients with dilated bile ducts, MR-cholangiography should be performed and hypergammaglobulinemia should also be screened for as autoantibodies for autoimmune liver disease. Liver MRI should be performed every year in children aged >5 years undergoing a monthly transfusion program in order to assess liver iron content. Iron chelation is recommended in case of iron overload but adhesion to chelator therapy is often low.44 Lastly, anti-hepatitis B immunization is mandatory.
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