Crigler-Najjar综合征的治疗进展

张文艳; 邓国宏

doi:10.3969/j.issn.1001-5256.2023.04.035

Crigler-Najjar综合征的治疗进展

DOI: 10.3969/j.issn.1001-5256.2023.04.035

张文艳^{1, 2},
邓国宏^2, , ,

1.
重庆大学生命科学学院，重庆 404100
2.
陆军军医大学第一附属医院感染科，重庆 400038

基金项目:

国家自然科学基金重点项目 (81930061);

西南医院重大技术创新计划重大项目 (SWH2016ZDCX1007)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：张文艳负责课题设计，撰写论文；邓国宏负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
邓国宏，gh_deng@hotmail.com (ORCID: 0000-0003-1263-7220)

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出版历程
- 收稿日期: 2022-08-14
- 录用日期: 2022-10-14
- 出版日期: 2023-04-20

Research advances in the treatment of Crigler-Najjar syndrome

Wenyan ZHANG^{1, 2},
Guohong DENG^{2
, ,
,}

1.
School of Life Sciences, Chongqing University, Chongqing 404100, China
2.
Department of Infectious Diseases, The First Affiliated Hospital of Army Medical University, Chongqing 400038, China

Research funding:

National Natural Science Foundation of China (81930061);

Key Project of the Technical Innovation Plan of Southwest Hospital (SWH2016ZDCX1007)

More Information

Corresponding author: DENG Guohong, gh_deng@hotmail.com (ORCID: 0000-0003-1263-7220)

摘要

摘要: Crigler-Najjar综合征(CNS)是一种因胆红素尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)活性降低或完全缺失所导致的血浆中非结合胆红素含量增加的常染色体隐性遗传病，分为CNS Ⅰ型和Ⅱ型。其中CNS Ⅰ型最为严重，可发展为核黄疸损坏大脑神经系统，甚至威胁到患者的生命。本文介绍了6种CNS治疗方法，包括光照疗法、血浆置换、药物治疗、肝移植、肝细胞移植和基因疗法；归纳了每种治疗技术的适用患者类型、治疗效果以及现存的不足之处。光照疗法、血浆置换、药物治疗和肝细胞移植治疗技术可暂时性地控制患者血清水平，降低患者发生核黄疸的风险，但不能彻底恢复UGT1A1酶活性；肝移植是CNS Ⅰ型患者目前唯一的治疗方式，但因合适肝脏供体来源和术后免疫排斥反应等因素受到限制；基因疗法在治疗CNS等遗传性疾病领域中最具应用前景，能够为CNS患者提供更多的可行性治疗方案。
- Crigler-Najjar综合征 /
- 光疗法 /
- 血浆置换 /
- 药物疗法 /
- 肝移植 /
- 细胞移植 /
- 基因治疗
Abstract: Crigler-Najjar syndrome (CNS) is an autosomal recessive disorder in which the content of plasma unconjugated bilirubin is increased due to the reduction or complete deficiency of the activity of bilirubin uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), classified as CNS type Ⅰ and Ⅱ. CNS type Ⅰ is the most severe, which will develop into kernicterus, damage the brain nervous system, and even threaten the life of patients. This article introduces six CNS treatment techniques, including phototherapy, plasma exchange, drug therapy, liver transplantation, hepatocyte transplantation and gene therapy. The applicable patient types, treatment effects and existing deficiencies of each technique were summarized. Phototherapy, plasma exchange, drug therapy and hepatocyte transplantation can temporarily control serum levels and reduce the risk of jaundice, but cannot completely restore UGT1A1 enzyme activity; liver transplantation is currently the only treatment option for CNS type Ⅰ patients, but is limited by suitable liver donors and post-operative immune rejection. Gene therapy has the most promising application in the treatment of genetic disorders such as CNS, which can provide more viable therapeutic techniques for CNS patients.
- Crigler-Najjar Syndrome /
- Phototherapy /
- Plasma Exchange /
- Drug Therapy /
- Liver Transplantation /
- Cell Transplantation /
- Genetic Therapy

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参考文献(45)

[1]	BHANDARI J, THADA PK, YADAV D. Crigler Najjar syndrome[M]. Treasure Island (FL): StatPearls Publishing, 2022.
[2]	CRIGLER JF Jr, NAJJAR VA. Congenital familial nonhemolytic jaundice with kernicterus[J]. Pediatrics, 1952, 10(2): 169-180.
[3]	ARIAS IM. Chronic unconjugated hyperbilirubinemia without overt signs of hemolysis in adolescents and adults[J]. J Clin Invest, 1962, 41(12): 2233-2245. DOI: 10.1172/JCI104682.
[4]	GAILITE L, VALENZUELA-PALOMO A, SANOGUERA-MIRALLES L, et al. UGT1A1 variants c. 864+5G > T and c. 996+2_996+5del of a Crigler-Najjar patient induce aberrant splicing in minigene assays[J]. Front Genet, 2020, 11: 169. DOI: 10.3389/fgene.2020.00169.
[5]	MEMON N, WEINBERGER BI, HEGYI T, et al. Inherited disorders of bilirubin clearance[J]. Pediatr Res, 2016, 79(3): 378-386. DOI: 10.1038/pr.2015.247.
[6]	TCACIUC E, PODUREAN M, TCACIUC A. Management of Crigler-Najjar syndrome[J]. Med Pharm Rep, 2021, 94(Suppl 1): S64-S67. DOI: 10.15386/mpr-2234.
[7]	CANU G, MINUCCI A, ZUPPI C, et al. Gilbert and Crigler Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database[J]. Blood Cells Mol Dis, 2013, 50(4): 273-280. DOI: 10.1016/j.bcmd.2013.01.003.
[8]	LEE WS, MCKIERNAN PJ, BEATH SV, et al. Bile bilirubin pigment analysis in disorders of bilirubin metabolism in early infancy[J]. Arch Dis Child, 2001, 85(1): 38-42. DOI: 10.1136/adc.85.1.38.
[9]	LUND HT, JACOBSEN J. Influence of phototherapy on the biliary bilirubin excretion pattern in newborn infants with hyperbilirubinemia[J]. J Pediatr, 1974, 85(2): 262-267. DOI: 10.1016/s0022-3476(74)80408-7.
[10]	YOHANNAN MD, TERRY HJ, LITTLEWOOD JM. Long term phototherapy in Crigler-Najjar syndrome[J]. Arch Dis Child, 1983, 58(6): 460-462. DOI: 10.1136/adc.58.6.460.
[11]	STRAUSS KA, ROBINSON DL, VREMAN HJ, et al. Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease[J]. Eur J Pediatr, 2006, 165(5): 306-319. DOI: 10.1007/s00431-005-0055-2.
[12]	EBRAHIMI A, RAHIM F. Crigler-Najjar syndrome: Current perspectives and the application of clinical genetics[J]. Endocr Metab Immune Disord Drug Targets, 2018, 18(3): 201-211. DOI: 10.2174/1871530318666171213153130.
[13]	DHAWAN A, LAWLOR MW, MAZARIEGOS GV, et al. Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives[J]. J Gastroenterol Hepatol, 2020, 35(4): 530-543. DOI: 10.1111/jgh.14853.
[14]	AHMED P, PRATT A, LAND VJ, et al. Multiple plasma exchanges successfully maintain a young adult patient with Crigler-Najjar syndrome type Ⅰ[J]. J Clin Apher, 1989, 5(1): 17-20. DOI: 10.1002/jca.2920050107.
[15]	DUAN ZJ, LI LL, JU J, et al. Treatment of hyperbilirubinemia with blood purification in China[J]. World J Gastroenterol, 2006, 12(46): 7467-7471. DOI: 10.3748/wjg.v12.i46.7467.
[16]	SUGATANI J, KOJIMA H, UEDA A, et al. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR[J]. Hepatology, 2001, 33(5): 1232-1238. DOI: 10.1053/jhep.2001.24172.
[17]	ABDUL RAFFAY E, LIAQAT A, KHAN M, et al. A rare case report of Crigler Najjar syndrome type Ⅱ[J]. Cureus, 2021, 13(1): e12669. DOI: 10.7759/cureus.12669.
[18]	GUERCIOLINI R. Mode of action of orlistat[J]. Int J Obes Relat Metab Disord, 1997, 21(Suppl 3): S12-S23.
[19]	KOTAL P, van der VEERE CN, SINAASAPPEL M, et al. Intestinal excretion of unconjugated bilirubin in man and rats with inherited unconjugated hyperbilirubinemia[J]. Pediatr Res, 1997, 42(2): 195-200. DOI: 10.1203/00006450-199708000-00011.
[20]	CLARENBURG R, KAO CC. Shared and separate pathways for biliary excretion of bilirubin and BSP in rats[J]. Am J Physiol, 1973, 225(1): 192-200. DOI: 10.1152/ajplegacy.1973.225.1.192.
[21]	HAFKAMP AM, HAVINGA R, OSTROW JD, et al. Novel kinetic insights into treatment of unconjugated hyperbilirubinemia: phototherapy and orlistat treatment in Gunn rats[J]. Pediatr Res, 2006, 59(4 Pt 1): 506-512. DOI: 10.1203/01.pdr.0000203180.79636.98.
[22]	HAFKAMP AM, HAVINGA R, SINAASAPPEL M, et al. Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats[J]. Hepatology, 2005, 41(3): 526-534. DOI: 10.1002/hep.20589.
[23]	HAFKAMP AM, NELISSE-HAAK R, SINAASAPPEL M, et al. Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar disease: a randomized controlled trial[J]. Pediatr Res, 2007, 62(6): 725-730. DOI: 10.1203/PDR.0b013e3181598cc5.
[24]	van der VEERE CN, SCHOEMAKER B, van der MEER R, et al. Rapid association of unconjugated bilirubin with amorphous calcium phosphate[J]. J Lipid Res, 1995, 36(8): 1697-1707.
[25]	van der VEERE CN, JANSEN PL, SINAASAPPEL M, et al. Oral calcium phosphate: a new therapy for Crigler-Najjar disease?[J]. Gastroenterology, 1997, 112(2): 455-462. DOI: 10.1053/gast.1997.v112.pm9024299.
[26]	SHANMUGAM NP, PERUMALLA R, GOPINATH R, et al. Auxiliary liver transplantation: a form of gene therapy in selective metabolic disorders[J]. J Clin Exp Hepatol, 2011, 1(2): 118-120. DOI: 10.1016/S0973-6883(11)60132-1.
[27]	WOLFF H, OTTO G, GIEST H. Liver transplantation in Crigler-Najjar syndrome. A case report[J]. Transplantation, 1986, 42(1): 84. DOI: 10.1097/00007890-198607000-00018.
[28]	OZÇAY F, ALEHAN F, SEVMIŞ S, et al. Living related liver transplantation in Crigler-Najjar syndrome type 1[J]. Transplant Proc, 2009, 41(7): 2875-2877. DOI: 10.1016/j.transproceed.2009.07.025.
[29]	RIBES-KONINCKX C, IBARS EP, CALZADO AMÁ, et al. Clinical outcome of hepatocyte transplantation in four pediatric patients with inherited metabolic diseases[J]. Cell Transplant, 2012, 21(10): 2267-2282. DOI: 10.3727/096368912X637505.
[30]	ANDERSON TN, ZARRINPAR A. Hepatocyte transplantation: past efforts, current technology, and future expansion of therapeutic potential[J]. J Surg Res, 2018, 226: 48-55. DOI: 10.1016/j.jss.2018.01.031.
[31]	AMBROSINO G, VAROTTO S, STROM SC, et al. Isolated hepatocyte transplantation for Crigler-Najjar syndrome type 1[J]. Cell Transplant, 2005, 14(2-3): 151-157. DOI: 10.3727/000000005783983250.
[32]	KHAN AA, PARVEEN N, MAHABOOB VS, et al. Treatment of Crigler-Najjar syndrome type 1 by hepatic progenitor cell transplantation: a simple procedure for management of hyperbilirubinemia[J]. Transplant Proc, 2008, 40(4): 1148-1150. DOI: 10.1016/j.transproceed.2008.03.022.
[33]	LYSY PA, NAJIMI M, STEPHENNE X, et al. Liver cell transplantation for Crigler-Najjar syndrome type Ⅰ: update and perspectives[J]. World J Gastroenterol, 2008, 14(22): 3464-3470. DOI: 10.3748/wjg.14.3464.
[34]	FOLLENZI A, SANTAMBROGIO L, ANNONI A. Immune responses to lentiviral vectors[J]. Curr Gene Ther, 2007, 7(5): 306-315. DOI: 10.2174/156652307782151515.
[35]	SOMANATHAN S, CALCEDO R, WILSON JM. Adenovirus-antibody complexes contributed to lethal systemic inflammation in a gene therapy trial[J]. Mol Ther, 2020, 28(3): 784-793. DOI: 10.1016/j.ymthe.2020.01.006.
[36]	MAESTRO S, WEBER ND, ZABALETA N, et al. Novel vectors and approaches for gene therapy in liver diseases[J]. JHEP Rep, 2021, 3(4): 100300. DOI: 10.1016/j.jhepr.2021.100300.
[37]	COLLAUD F, BORTOLUSSI G, GUIANVARC'H L, et al. Preclinical development of an AAV8-hUGT1A1 vector for the treatment of Crigler-Najjar syndrome[J]. Mol Ther Methods Clin Dev, 2019, 12: 157-174. DOI: 10.1016/j.omtm.2018.12.011.
[38]	YAN Z, YAN H, OU H. Human thyroxine binding globulin (TBG) promoter directs efficient and sustaining transgene expression in liver-specific pattern[J]. Gene, 2012, 506(2): 289-294. DOI: 10.1016/j.gene.2012.07.009.
[39]	de CANEVA A, PORRO F, BORTOLUSSI G, et al. Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases[J]. JCI Insight, 2019, 5(15): e128863. DOI: 10.1172/jci.insight.128863.
[40]	BOMMINENI VR, CHOWDHURY NR, WU GY, et al. Depolymerization of hepatocellular microtubules after partial hepatectomy[J]. J Biol Chem, 1994, 269(40): 25200-25205. DOI: 10.1016/s0021-9258(17)31517-x.
[41]	KREN BT, PARASHAR B, BANDYOPADHYAY P, et al. Correction of the UDP-glucuronosyltransferase gene defect in the Gunn rat model of Crigler-Najjar syndrome type Ⅰ with a chimeric oligonucleotide[J]. Proc Natl Acad Sci U S A, 1999, 96(18): 10349-10354. DOI: 10.1073/pnas.96.18.10349.
[42]	FISCHER D, LI Y, AHLEMEYER B, et al. In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis[J]. Biomaterials, 2003, 24(7): 1121-1131. DOI: 10.1016/s0142-9612(02)00445-3.
[43]	APGAR JF, TANG JP, SINGH P, et al. Quantitative systems pharmacology model of hUGT1A1-modRNA encoding for the UGT1A1 enzyme to treat Crigler-Najjar syndrome type 1[J]. CPT Pharmacometrics Syst Pharmacol, 2018, 7(6): 404-412. DOI: 10.1002/psp4.12301.
[44]	BORTOLUSSI G, MURO AF. Advances in understanding disease mechanisms and potential treatments for Crigler-Najjar syndrome[J]. Expert Opin Orphan D, 2018, 6(7): 425-439. DOI: 10.1080/21678707.2018.1495558.
[45]	AN D, SCHNELLER JL, FRASSETTO A, et al. Systemic messenger RNA therapy as a treatment for methylmalonic acidemia[J]. Cell Rep, 2017, 21(12): 3548-3558. DOI: 10.1016/j.celrep.2017.11.081.