The linear effects of α‐thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease

Vasavda, Nisha; Menzel, Stephan; Kondaveeti, Sheila; Maytham, Emma G.; Awogbade, Moji; Bannister, Sybil; Cunningham, Juliette; Eichholz, Andrew; Daniel, Yvonne; Okpala, Iheanyi; Fulford, Tony; Thein, Swee Lay

doi:10.1111/j.1365-2141.2007.06643.x

Cited by 77 publications

(52 citation statements)

References 19 publications

(29 reference statements)

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“…Though less common than (TA) 6 and (TA) 7 repeats, they were identified in 25% of genotyped CSSCD children. A linear relationship between the number of tandem repeats and UGT1A1 gene activity was reported [15], and studies primarily in adults with SCA confirm this trend [18][19][20]. This relationship has been shown to overcome the well-documented protection of a-thalassemia in the development of cholelithiasis in a population of SCA patients with a predominantly Benin ß s haplotype [21].…”

Section: Discussionmentioning

confidence: 91%

UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia

et al. 2008

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Genetic modifiers contribute to phenotypic variability in patients with sickle cell anemia (SCA). The influence of the bilirubin UDP-glucuronosyltransferase (UGT) 1A1 (TA) n TAA promoter polymorphism on bilirubin levels and gallbladder disease in SCA was examined using prospectively collected data from the Cooperative Study of Sickle Cell Disease. A total of 324 children with HbSS (median age 6.9 years) had UGT1A1 genotyping; 243 (75%) had common (TA) 6 or (TA) 7 alleles, whereas 81 (25.0%) had variant (TA) 5 or (TA) 8 alleles. The UGT1A1 genotype significantly influenced average bilirubin levels for the common alleles: 6/6 genotype 5 2.36 ± 1.13 mg/dL, 6/7 genotype 5 2.90 ± 1.54 mg/dL, and 7/7 genotype 5 4.24 ± 2.11 mg/dL (P < 0.0001). Thirty-nine percent of children with the 7/7 genotype had documented gallbladder disease, compared with 18.2% with the 6/7 genotype and only 9.9% with the wildtype 6/6 UGT1A1 genotype (P 5 0.001). To analyze the (TA) 5 and (TA) 8 variant alleles, three groups were generated, showing increasing bilirubin levels with increasing TA repeats and age. Group 3 (genotypes 6/8, 7/7, and 7/8) had a significantly greater rate of bilirubin change than Groups 1 (genotypes 5/6, 5/7, and 6/6) or 2 (genotype 6/7). These results validate previous smaller studies and confirm that the UGT1A1 promoter polymorphism exerts a powerful influence on bilirubin levels and the development of gallbladder disease in children with SCA. UGT1A1 genotyping should be considered as a screening tool for predicting children most likely to develop gallbladder disease at a young age. Am. J. Hematol. 83:800-803, 2008. V

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Section: Discussionmentioning

confidence: 91%

UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia

et al. 2008

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“…Furthermore, Chaar et al (2006) showed that although a-thalassaemia is associated with a modest reduction in haemolysis and unconjugated bilirubin level, UGT1A1 polymorphism outweighs its effect on cholelithogenesis in SCD patients predominantly of Benim bS haplotype (Chaar et al 2006). Vasavda et al (2007) also observed that a-thalassaemia was significantly associated with reduced bilirubin levels in SCD adult patients. In our young SCD patient series predominantly of Bantu bS haplotype, we found that the coinheritance of a-thalassaemia does not significantly influence Hb level, total bilirubin level, cholelithogenesis and the need for cholecystectomy (Table 3).…”

Section: Discussionmentioning

confidence: 98%

Early modification of sickle cell disease clinical course by UDP-glucuronosyltransferase 1A1 gene promoter polymorphism

et al. 2008

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Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinaemia and, in a subset of patients, cholelithiasis occurs. We investigated whether the (TA) n promoter polymorphism in the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) may modify bilirubin metabolism, influencing bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in a group of 153 young SCD patients (mean age 12.0 ± 9.0 years) predominantly of Bantu beta S haplotype. The concomitant effect of alpha thalassaemia was also analysed. Among the several UGT1A1 genotypes found, the most frequent were the (TA) 6 /(TA) 6 (n = 37), (TA) 6 /(TA) 7 (n = 60) and (TA) 7 /(TA) 7 (n = 29). These groups of patients did not significantly differ in age, gender ratio and haemoglobin, foetal haemoglobin and reticulocyte levels. On the other hand, total bilirubin levels were significantly different between groups, with an increased (TA) repeat number being associated with higher bilirubinaemia. Furthermore, both cholelithiasis and cholecystectomy were more frequent in groups with higher (TA) repeat number, although the former association was not statistically significant. None of the mentioned parameters is statistically different within UGT1A1 groups with the presence of alpha thalassaemia. Thus, the UGT1A1 promoter polymorphism may represent an important nonglobin genetic modifier of Bantu SCD patients' clinical manifestations, even at a young age.

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“…14 It is also debatable if patients who have coinherited Gilbert syndrome (polymorphism in promoter region of UGT1A gene) and thus are genetically predisposed to further increases in serum bilirubin levels, and gallstones, 15 should have elective cholecystectomy.…”

Section: 3mentioning

confidence: 99%

How we treat sickle hepatopathy and liver transplantation in adults

Gardner

Suddle²,

Kane

et al. 2014

Blood

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Sickle cell disease (SCD) has evolved into a debilitating disorder with emerging end-organ damage. One of the organs affected is the liver, causing “sickle hepatopathy,” an umbrella term for a variety of acute and chronic pathologies. Prevalence of liver dysfunction in SCD is unknown, with estimates of 10%. Dominant etiologies include gallstones, hepatic sequestration, viral hepatitis, and sickle cell intrahepatic cholestasis (SCIC). In addition, causes of liver disease outside SCD must be identified and managed. SCIC is an uncommon, severe subtype, with outcome of its acute form having vastly improved with exchange blood transfusion (EBT). In its chronic form, there is limited evidence for EBT programs as a therapeutic option. Liver transplantation may have a role in a subset of patients with minimal SCD-related other organ damage. In the transplantation setting, EBT is important to maintain a low hemoglobin S fraction peri- and posttransplantation. Liver dysfunction in SCD is likely to escalate as life span increases and patients incur incremental transfusional iron overload. Future work must concentrate on not only investigating the underlying pathogenesis, but also identifying in whom and when to intervene with the 2 treatment modalities available: EBT and liver transplantation.

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The linear effects of α‐thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease

Cited by 77 publications

References 19 publications

UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia

UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia

Early modification of sickle cell disease clinical course by UDP-glucuronosyltransferase 1A1 gene promoter polymorphism

How we treat sickle hepatopathy and liver transplantation in adults

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