Abstract 513

Background:

The accelerated hemolysis in SCA increases bilirubin excretion and the susceptibility to pigment gallstone formation. Uridine diphosphate-glucuronosyltransferase (UGT1A1) gene polymorphism and alpha-thalassemia are factors known to modify this risk. However, their relative influence and other factors such as SCA disease severity and the use of ceftriaxone for acute febrile episodes remain to be explored in a newborn cohort. The goal of this study was to define the cumulative incidence and risk factors for the occurrence of gallstones in a SCA-newborn-cohort.

Patients and Methods:

Alpha-genes, beta-globin haplotypes, UGT1AI genotype, G6PD-enzymatic activity were recorded; baseline biological parameters were determined during the second year of life, away from crises and transfusions as previously described (Blood 2011,117, 4). Annual check-ups including abdominal sonography were performed as soon as the age of 1 year. Cholecystectomy was systematically performed in the 6 months following the discovery and confirmation of presence of gallstones. All hospitalizations and their causes were prospectively recorded. Patients were censored on the date of gallstone occurrence or last abdominal sonography; event rates/year (pain crises, ACS, febrile episodes) were calculated, and KM-estimated cumulative risk for gallstones and Cox regression were used to assess the predictive factors for gallstones.

Results:

SCA-patients (364: 353 SS, 8 Sb0, 3 SDPunjab; 182 F,182 M) born before February 2010 and followed until the age of 18–20 years were included in this study. Alpha-thalassemia was present in 46% patients (available in 323; 2 genes: n=33; 3 genes: n=116; 4 genes: n=172; 5 genes: n=2); beta-haplotypes (available in 291) were Car/Car in 42.6%, Ben/Ben in 19.9%, Sen/Sen in 9.6%, and others in 27.8%. G6PD activity (available in 309) was deficient in 11.6%. UGTA1 polymorphism (available in 175) showed Gilbert genotype in 19.8%, i.e., 7/7 in 13.4% and 7/8 in 6.4%. The frequency of the other genotypes was: 5/6: 6.4%; 5/7:7%; 5/8:0.6%; 6/6:23.3%, 6/7:34.3%; and 6/8:8.1%. Unconjugated bilirubin values at baseline were significantly correlated with the total number of UGTA1A1 repeats (r=0.415, p<0.001). Mean rates (SD) of pain crises, ACS and acute febrile episodes were 0.56 (0.68), 0.12 (0.18), 0.34 (0.54), respectively. Gallstones were observed in 98/364 patients at the median age of 9.2 (range: 2.5 to 17.9 years). The cumulative risk of gallstones was 5% by age 5, 20.7% by age 10 and 35.6 % by age 15 and was not significantly different in patients with Gilbert polymorphism (Log Rank p=0.4) but was significantly related to the number of alpha-genes (Log-Rank p=0.039). However, the risk was significantly increased in patients homozygous or heterozygous for (TA8) (Log Rank p=0.016). Univariate Cox regression analysis showed that the number of alpha-genes was a significant risk factor (p=0.014) whereas G6PD deficiency, beta-haplotypes and Gilbert genotype were not significant risk factors; however, the presence of at least one allele (TA8) was a significant risk factor (p=0.025). Among the baseline biological parameters, hemoglobin, WBC, neutrophils, platelets, MCV, and bilirubin were not significant factors whereas HbF level (p=0.028), reticulocyte count (p<0.001) and LDH (p=0.020) significantly increased the risk for gallstones. Among clinical events, pain crises, ACS and febrile episodes significantly increased the risk (p<0.001). Multivariate Cox analysis including all the significant risk factors in the univariate analysis retained the deletion of 2 alpha genes (HR=4.66; 95% CI:1.11-19.52,p=0.035) which decreases the risk, the presence of at least one allele (TA8) (HR=2.26:95% CI:1.07-4.78, p=0.032), which increases the risk and the baseline reticulocytes count per 1×109/L increase(HR:1.001;1.000-1.002;p=0.005), as independent and significant predictive factors for gallstones.

Conclusion:

This prospective SCA newborn-cohort study shows that gallstones may begin as soon as 2.5 years of age and that the cumulative risk reaches a high 35.6% by age 15. The deletion of 2 alpha genes, the presence of at least one UGT1A1 (TA8) allele and high baseline reticulocyte count are independent and significant predictive factors showing that the risks are multifacturial and highly and primarily dependent on hemolysis

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.