Coexisting Gilbert's syndrome and sickle cell disease.

ABSTRACT

We report the coexistence of Gilbert's syndrome and homozygous sickle cell disease in a child with persistent unconjugated hyperbilirubinemia.

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GILBERT'S SYNDROME is a common benign hereditary disorder of bilirubin metabolism with a prevalence of 3% to 6% in the general population. (1) It is characterized by chronic, benign, intermittent jaundice without other clinical manifestations or abnormalities on liver microscopy. Attempts to explain persistent and severe unconjugated hyperbilirubinemia in our patient with sickle cell anemia led us to the diagnosis of Gilbert's syndrome. Coexistence of Gilbert's syndrome and sickle cell anemia has not been described before in literature.

CASE REPORT

The patient is a 16-year-old African American girl with homozygous sickle cell disease who was first brought to us at the age of 8 with acute gastroenteritis. She was pale and jaundiced with mild splenomegaly. Complete blood count revealed a white blood cell count of 19,900/[mm.sup.3], hemoglobin value of 8.4 g/dL, and platelet count 332,000/[mm.sup.3] with a normal differential. The reticulocyte count was 6.7%. She had unconjugated hyperbilirubinemia with total bilirubin level of 9.2 mg/dL and direct bilirubin level of 1.2 mg/dL with normal liver enzymes. Lactate dehydrogenase was elevated at 1,464 U/L. Hemoglobin electrophoresis revealed 89% HbS, 10.7% HbF, and 2.5% [HbA.sub.2]. A Kleihaeur-Betke test ruled out hereditary persistence of fetal hemoglobin. Serology for hepatitis A and B was negative. Findings on abdominal ultrasonography were normal except for mild splenomegaly. There was no evidence of gallstones. On subsequent visits, the patient continued to have significantly elevated levels of unconjugat ed bilirubin even in the absence of infections or sickle cell crisis. Cholelithiasis was detected at age 10, and an elective laparoscopic cholecystectomy was done at 12 years of age. She has had a relatively benign course related to her sickle cell disease. Growth and development of secondary sexual characteristics was normal. Jaundice was persistent, with indirect bilirubin levels as high as 16 mg/dL, but liver enzyme values remained normal. Results of serology for cytomegalovirus, Epstein-Barr virus, and hepatitis A, B, and C were negative. Serum copper and G6PD levels were normal. Uncommon causes of unconjugated hyperbilirubinemia were considered, and a diagnosis of Gilbert's syndrome was confirmed by DNA analysis using polymerase chain reaction, which revealed homozygosity for the A [(TA).sub.7] TAA allele of UGT1A1 gene.

DISCUSSION

Gilbert's syndrome is a benign familial condition of nonhemolytic unconjugated hyperbilirubinemia. (2) The diminished activity of the conjugating enzyme uridine diphosphate glucuronyl transferase (UGT1A1) is responsible for the decreased bilirubin conjugation and the resultant jaundice. (3)

Coexistence of Gilbert's syndrome and a variety of hemolytic anemias, including hereditary spherocytosis, (4-6) G6PD deficiency, (7-9) and heterozygous [beta] thalassemia (7,10) have been described. Patients with congenital dyserythropoietic anemia type II and concurrent Gilbert's syndrome have increased bilirubin levels with a higher incidence of gallstones. (11) Extensive review of the literature failed to yield any reported association of Gilbert's syndrome and sickle cell disease.

Jaundice and unconjugated hyperbilirubinemia are frequent in patients with sickle cell disease. Elevation of the bilirubin level with deepening of jaundice can occur from a variety of causes. Infections, vaso-occlusive episodes (especially with intrahepatic sickling), and viral hepatitis can all aggravate jaundice in sickle cell disease. Hemolysis induced by G6PD deficiency may enhance hyperbilirubinemia in rare cases. The average steady-state bilirubin levels are higher in the presence of cholelithiasis and may be further elevated during cholecystitis, cholangitis, or in the event of obstruction of the common bile duct by a gallstone. Our patient had persistent unconjugated hyperbilirubinemia in the absence of obvious causes. This prompted further investigations to rule out rare causes contributing to her jaundice. This is the first reported case of the coexistence of Gilbert's syndrome and sickle cell disease.

References

(1.) Owens D, Evans J: Population studies on Gilbert's syndrome. J Med Genet 1975; 12:152-156

(2.) Gilbert NA, Lereboulett P: La cholemic simple familiale. Semin Med (Paris) 1901; 11:241-243

(3.) Bosma PJ, Choudhury JR, Baker C, et al: The genetic basis of the reduced expression of bilirubin UDP glucuronyl-transferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333:1171

(4.) Sharma S, Vukelja SJ, Kadakia S: Gilbert's syndrome coexisting with and masking hereditary spherocytosis. Ann Hematol 1997; 74:287-289

(5.) Berk PD, Blaschke TF: Detection of Gilbert's syndrome in patients with hemolysis. Ann Intern Med 1972; 77:527-531

(6.) Katz ME, Weinstein IM: Extreme hyperbilirubinemia in a patient with hereditary spherocytosis, Gilbert's syndrome and obstructive jaundice. Am J Med Sci 1978; 275:373-379

(7.) Sampeitro M, Lupica L, Perrero L, et al: The expression of uridine diphosphate glucuronyltransferase gene is a major determinant of bilirubin level in heterozygous [beta] thalassemia and in G6PD deficiency. Br J Haematol 1997; 99:437

(8.) Kaplan M, Renbaum P, Levy-Lahad E, et al: Gilbert's syndrome and G6PD deficiency: a dose dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci USA 1997; 94:12128-12132

(9.) Iolascon A, Faienza MF, Moretti A, et al: UGT1 promoter polymorphism accounts for increased neonatal appearance of hereditary spherocytosis. Blood 1998; 91:1093

(10.) Galanello R, Persue L, Melis MA, et al: Hyperbilirubinemia in heterozygous [beta] thalassemia is related to coinherited Gilbert's syndrome. Br J Haematol 1997; 99:433

(11.) Perrotta S, Miraglia del Guidice E, Carbone R, et al: Gilbert's syndrome accounts for the phenotypic variability of congenital dyserythropoeitic anemia type II (CDA-II). J Pediatr 2000; 136:556-559

RELATED ARTICLE: KEY POINTS

* Hyperbilirubinemia is common in sickle cell disease.

* Chronic, persistent hyperbilirubinemia after cholecystectomy raised suspicion of other etiologic factors.

* Gilbert's disease can cause chronic, intermittent, benign hyperbilirubinemia.

From the Department of Pediatric Hematology/Oncology, Children's Hospital of New Orleans and Louisiana State University Health Science Center.

Reprint requests to Raj Warrier, MD, Louisiana State University Health Science Center, Department of Pediatric Hematology/Oncology, 1542 Tulane Ave, New Orleans, LA 70112.