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Gilbert's syndrome is caused by a reduction in the activity of uridine diphosphate glucuronosyltransferase (UGT) and induces chronic, non-hemolytic ...
J Korean Soc Neonatol • 2010;17:266-9

Case report doi: 10.5385/jksn.2010.17.2.266 pISSN 1226-1513•eISSN 2093-7849

A Case of Gilbert’s Syndrome with Severe Neonatal Hyperbilirubinemia Ye-Seul Hong, M.D., Jang-Yong Jin, M.D., and Woo-Ryoung Lee, M.D.

Department of Pediatrics, Soonchunhyang University Hospital, Seoul, Korea

Gilbert’s syndrome is caused by a reduction in the activity of uridine diphosphate glucuronosyltransferase (UGT) and induces chronic, non-hemolytic unconjugated hyperbilirubinemia. It has been suggested that 3-10% of the population has Gilbert’s syndrome. Commonly, Gilbert’s syndrome causes mild symptoms. However, a case of Gilbert’s syndrome with severe neonatal hyperbilirubinemia is presented here. The patient developed jaundice three days after birth. Five days after birth, the patient’s total serum bilirubin level was 34 mg/dL. The patient received intensive phototherapy and was given oral phenobarbital. Hemolytic hyperbilirubinemia was excluded on the basis of laboratory tests. Heterozygote polymorphisms of the promoter region (-3279T>G) and exon 1 (211G>A) were found in UGT1A1 gene. After discharge, the patient did not require any further treatment. This is the first case of proven Gilbert’s syndrome with severe neonatal hyperbilirubinemia in Korea. Key Words: Gilbert disease, Gilbert’s syndrome, Newborn, Hyperbilirubinemia

Introduction

neonatal jaundice3, 5). Here, a case of Gilbert’s syndrome in a neonate with severe hyperbilirubinemia is reported.

Gilbert’s syndrome is a chronic, non-hemolytic uncon­ jugated hyperbilirubinemia caused by a reduction in the activity of uridine diphosphate glucuronosyltransferase

Case report

(UGT). UGT plays a critical role in the detoxification of bilirubin by conjugating it with glucuronic acid1-3). Three

A 5-day-old girl was admitted via the outpatient de­

grades of UGT1A1 deficiency occur in humans: Crigler-

partment with a yellowish change of skin color two days

Najjar syndrome type 1, 2, and Gilbert’s syndrome. Among

prior to admission. Her activity and crying were not

these, Gilbert’s syndrome is the mildest form. In patients

decreased. On the physical examination, the weight was

with Gilbert’s syndrome the serum bilirubin levels fluctuate

3,430 g and the height 51 cm. The pulse rate was 145/min,

from normal to 5 mg/dL. The levels may be higher in the

the respiratory rate was 45/min, and the body temperature

presence of hemolysis and increase with fasting, stress or

was 36.8℃. The patient had icteric sclera and face, abdomen

4)

infection . In most cases of Gilbert’s syndrome the symp­

and feet. Laboratory studies revealed a hemoglobin level of

toms are mild, but it may be associated with exaggerated

15.9 g/dL, a white blood cell count of 12,200/mm3, and a

Received: 16 September 2010, Revised: 8 October 2010, Accepted: 24 October 2010 Correspondence to Woo-Ryoung Lee, M.D. Department of Pediatrics, Soonchunhyang University Hospital, 22 Daesagwan-gil, Yongsan-gu, Seoul 140-887, Korea Tel: +82-2-709-9351, Fax: +82-2-794-5471, E-mail: [email protected]

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Copyright © 2010 by the Korean Society of Neonatology • Published by the Korean Society of Neonatolog. All rights reserved.



J Korean Soc Neonatol 2010;17:266-9 • doi: 10.5385/jksn.2010.17.2.266

platelet count of 381,000/mm3. The reticulocyte count was

267

Discussion

3.3% and the corrected reticulocyte count was 3.4%. The total serum bilirubin level was 34 mg/dL, direct bilirubin was

The reduction of UGT1A1 activity causes unconjugated

1.4 mg/dL, aspartate aminotransferase was 30 U/L, alanine

hyperbilirubinemia as observed in the Crigler-Najjar

aminotransferase was 11 U/L and gamma-glutamyl­

syndrome and Gilbert’s syndrome. The mutations of the

transferase was 43 U/L. The electrolyte levels were within

UGT1A1 gene are associated with clinical hyperbiliru­

normal ranges. Viral serology (toxoplasma, rubella,

binemia. Genetic abnormalities causing an absence of

cytomegalovirus, herpes simplex and syphilis) was not

UGT1A1 activity result in Crigler-Najjar syndrome type 1,

performed, but blood and urine cultures were normal.

which is characterized by potentially lethal hyperbiliru­

Abdomen and brain ultrasonography were performed, and

binemia. In addition, mutations causing a severe but

the results were normal. The blood type was B Rh positive

incomplete reduction of UGT1A1 activity result in Crigler-

and her mother’s blood type was O Rh positive. The

Najjar syndrome type 2, which is characterized by inter­

peripheral blood smear findings showed no evidence of

mediate levels of hyperbilirubinemia. In Gilbert’s syndrome,

hemolytic anemia. The result of Coombs’ test was negative.

UGT1A1 activity is reduced to approximately 30% of the

Overt hemolysis was excluded on the basis of normal

normal levels. Gilbert’s syndrome is characterized by a mild

hemoglobin values, reticulocyte counts, and the results of

and chronic unconjugated hyperbilirubinemia2, 6, 7).

peripheral blood smear and direct Coombs’ test.

However, it may be associated with exaggerated neonatal

An intensive phototherapy was started, and the total

hyperbilirubinemia if other risk factors such as prolonged

serum bilirubin level was assessed every three to four hours

fasting, surgery, and infection are present. The UGT1A1 gene

on the first hospital day. The total serum bilirubin level fell to

consists of a promoter region and exon region. A mutation of

29.7 mg/dL after three hours of treatment and to 28.4 mg/dL

the promoter region is principally known to be associated

after four hours of further treatment. On the second hospital

with Gilbert’s syndrome, and a mutation of the exon region is

day, the total serum bilirubin level was 24.6 mg/dL. The

known to be associated with Crigler-Najjar syndrome.

patient was also treated with oral phenobarbital in addition

However, UGT1A1 mutations are appeared to be variable

to the intensive phototherapy. The total serum bilirubin level

among different ethnic groups6, 8). A part of exon 1

decreased gradually afterward. The level was 10.2 mg/dL on

containing the 211G>A (G71R) has been reported to be

the seventh hospital day, finally falling to tolerable levels. The patient was discharged without medication after stabilization of the total serum bilirubin level. The total serum bilirubin level has remained below 1 mg/dL, despite infection such as acute bronchiolitis and a urinary tract infection. Genetic studies were performed for the evaluation of the cause of the severe hyperbilirubinemia. Genomic DNA was isolated from lymphocytes, and the exons and the promoter regions of the UGT1A1 gene were amplified using polymerase chain reaction. Mutation analysis of the UGT1A1 gene revealed that the patient had compound heterozygosity for two different polymorphisms in the promoter region (-3279T>G) and in exon 1 (211G>A) (Fig. 1).

Fig. 1. Nucleotide sequences. This figures show the mutations in the promoter region (-3279T>G) (A), and in exon 1 (211G>A) (B).

268

YS Hong, et al. • Gilbert's Syndrome with Severe Neonatal Hyperbilirubinemia

associated with Gilbert’s syndrome in the Asian population,

을 위해 포합시키는 기능을 가진 효소인 uridine diphosphate

while Gilbert’s syndrome in Caucasians is more commonly

glucuronosyltransferase (UGT)의 활성도 감소에 의해 야기되

3, 6-9)

associated with the TA7 mutation

. In this case,

며 만성, 비용혈성, 비포합 고빌리루빈혈증을 유발한다. 대부분

heterozygous polymorphisms were identified in the

경증의 증상을 보이며 인구의 3-10%에서 나타나는 것으로 알

UGT1A1 gene promoter (-3279T>G) region and exon 1

려져 있다. 치료로 페노바비탈(phenobarbital)을 투여할 수 있

(211G>A) region, which has previously been reported to be

으며 이 페노바비탈은 UGT 효소활성도를 증가시켜 혈중 빌리

associated with Gilbert’s syndrome in the Asian population.

루빈 농도를 떨어뜨린다. 본 증례에서는 일반적인 경우와 달리

Gilbert’s syndrome is commonly associated with mild

심한 신생아 황달이 동반된 Gilbert 증후군을 기술하였다. 환아

symptoms. However, in this case, severe neonatal jaundice

는 생후 2-3일경부터 황달 소견을 보였으며 생후 5일경 혈중 총

developed. Hemolysis and inflammation were excluded.

빌리루빈 수치가 34 mg/dL로 높게 상승되어 있어 집중적인 광

Liver enzyme was normal. But less frequent causes of

선치료의 시행과 함께 경구 페노바비탈을 투여 받았다. 검사실

unconjugated hyperbilirubinemia, such as ineffective

소견에서 정상 혈색소, 망상적혈구 수치 보였으며 direct

erythropoiesis, cardiac disease, rhabdomyolysis and drugs

Coombs’ test 에서도 정상 소견 보여 용혈성 고빌리루빈혈증은

were not evaluated. In Crigler-Najjar syndrome type 1,

제외하였으며 이후 시행한 유전자 검사에서 UGT1A1 유전자의

treatment with exchange transfusions is effective and liver

-3279T>G, 211G>A 변이가 발견되어 Gilbert 증후군으로 진단되

transplantation is the only definitive therapy. In Crigler-Najjar

었다. 광선치료와 경구 페노바비탈 투여로 혈중 총 빌리루빈 농

syndrome type 2, continuous treatment with phenobarbital

도의 지속적 감소를 보여 퇴원하였으며 이후 외래검사상 총 빌

is usually needed. The -3279T>G mutation of UGT1A1

리루빈 수치는 안정적이었다. 저자들은 심한 신생아 황달을 보

reduces transferase activity to 40% of the normal level. This

인 Gilbert 증후군의 예를 보고하는 바이다.

mutation in Crigler-Najjar syndrome type 2 has been previously reported10). The hyperbilirubinemia associated with the -3279T>G mutation responds well to phenobarbital

References

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한글요약

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