合并炎症性肠病的糖原累积病-Ⅰb型5例患儿SGLT2抑制剂治疗效果分析

doi:10.12372/jcp.2023.22e0095

临床儿科杂志 ›› 2023, Vol. 41 ›› Issue (4): 294-299.doi: 10.12372/jcp.2023.22e0095

合并炎症性肠病的糖原累积病-Ⅰb型5例患儿SGLT2抑制剂治疗效果分析

夏瑜¹, 葛文松², 杜陶子¹, 龚自珍¹, 肖冰¹, 梁黎黎¹, 王瑞芳¹, 杨奕¹, 邱文娟¹()

1.儿内分泌遗传科上海交通大学医学院附属新华医院（上海 200092）
2.消化科上海交通大学医学院附属新华医院（上海 200092）

收稿日期:2022-12-17 出版日期:2023-04-15 发布日期:2023-04-07
通讯作者: 邱文娟 E-mail:qiuwenjuan@xinhuamed.com.cn
基金资助:
国家重点研发计划(2022YFC2703400);上海市交通大学医学院儿科学院先天性肾上腺皮质功能不全临床研究中心(ELYZX202106)

Therapeutic efficacy of an SGLT2 inhibitor in five pediatric patients with glycogen storage disease type Ⅰb and inflammatory bowel disease

XIA Yu¹, GE Wensong², DU Taozi¹, GONG Zizhen¹, XIAO Bing¹, LIANG Lili¹, WANG Ruifang¹, YANG Yi¹, QIU Wenjuan¹()

1. Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
2. Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

Received:2022-12-17 Online:2023-04-15 Published:2023-04-07
Contact: QIU Wenjuan E-mail:qiuwenjuan@xinhuamed.com.cn

摘要/Abstract

摘要：

目的分析5例合并炎症性肠病（IBD）的糖原累积病-Ⅰb型（GSD-Ⅰb）患儿接受钠-葡萄糖共转运体2（SGLT2）抑制剂的治疗效果。方法回顾性分析2021—2022年接受治疗并随访的5例合并IBD的GSD-Ⅰb型患儿，SGLT2抑制剂治疗前后的临床表现、实验室及辅助检查。结果 5例患儿IBD发作中位年龄为5.0岁。5例均有口腔溃疡、腹痛、腹泻及肛周脓肿。SGLT2抑制剂治疗前，5例的中位儿童克罗恩病活动指数（PCDAI）为55.0。SGLT2抑制剂中位治疗12.0月后[末次随访中位剂量0.31 mg/(kg·d)]，中位PCDAI（10.0）显著降低（P=0.043），5例均获得临床应答。治疗中，2例出现低血糖，4例出现会阴部或尿道口瘙痒。发现2种新SLC37A4变异（c.2delT，c.1065delG）。c.446G>A（p.G149E）为热点变异（70%）。结论 SGLT2抑制剂可明显改善GSD-Ⅰb型患儿的IBD活动度，且安全性良好。

关键词: 糖原累积病-Ⅰb型, SLC37A4基因, 炎症性肠病, 中性粒细胞减少症, SGLT2抑制剂

Abstract:

Objective To analyze the therapeutic effect of a sodium-glucose co-transporter 2 (SGLT2) inhibitor in five pediatric patients with glycogen storage disease type Ⅰb (GSD-Ⅰb) and inflammatory bowel disease (IBD). Methods Changes in clinical manifestations and laboratory tests of five pediatric GSD-Ⅰb patients with IBD before and after the administration of a SGLT2 inhibitor from 2021 to 2022 were analyzed retrospectively. Results The median age of IBD onset was 5.0 years old. All five patients presented with oral ulcers, abdominal pain, diarrhea and perianal abscess. Before the administration of the SGLT2 inhibitor, the median pediatric Crohn’s disease activity index (PCDAI) was 55.0. After the treatment [median length of treatment: 12.0 months, median dose at the last follow-up: 0.31 mg/(kg·d)], the median PCDAI (10.0) was significantly decreased (P=0.043), and all the patients achieved clinical response. During the treatment, 2 patients developed hypoglycemia and 4 patients developed pruritus in perineum or urethral orifice. Two novel SLC37A4 variants were identified (c.2delT, c.1065delG) and c.446G>A (p.G149E) was a hotspot variant (70%). Conclusions The SGLT2 inhibitor can significantly and safely reduce the disease activity of IBD in pediatric GSD-Ⅰb patients.

Key words: glycogen storage disease type Ⅰb, SLC37A4 gene, inflammatory bowel disease, neutropenia, SGLT2 inhibitor

夏瑜, 葛文松, 杜陶子, 龚自珍, 肖冰, 梁黎黎, 王瑞芳, 杨奕, 邱文娟. 合并炎症性肠病的糖原累积病-Ⅰb型5例患儿SGLT2抑制剂治疗效果分析[J]. 临床儿科杂志, 2023, 41(4): 294-299.

XIA Yu, GE Wensong, DU Taozi, GONG Zizhen, XIAO Bing, LIANG Lili, WANG Ruifang, YANG Yi, QIU Wenjuan. Therapeutic efficacy of an SGLT2 inhibitor in five pediatric patients with glycogen storage disease type Ⅰb and inflammatory bowel disease[J]. Journal of Clinical Pediatrics, 2023, 41(4): 294-299.

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参考文献 21

[1]	Chou JY, Jun HS, Mansfield BC. Glycogen storage disease type I and G6Pase-beta deficiency: etiology and therapy[J]. Nat Rev Endocrinol, 2010, 6: 676-688. doi: 10.1038/nrendo.2010.189
[2]	Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics[J]. Genet Med, 2014, 16: e1. doi: 10.1038/gim.2014.128 pmid: 25356975
[3]	Chou JY, Jun HS, Mansfield BC. Neutropenia in type Ib glycogen storage disease[J]. Curr Opin Hematol, 2010, 17: 36-42. doi: 10.1097/MOH.0b013e328331df85 pmid: 19741523
[4]	Grunert SC, Elling R, Maag B, et al. Improved infla-mmatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin in glycogen storage disease type Ib[J]. Orphanet J Rare Dis, 2020, 15: 218 doi: 10.1186/s13023-020-01503-8
[5]	Dale DC, Bolyard AA, Marrero T, et al. Neutropenia in glycogen storage disease Ib: outcomes for patients treated with granulocyte colony-stimulating factor[J]. Curr Opin Hematol, 2019, 26:16-21. doi: 10.1097/MOH.0000000000000474 pmid: 30451720
[6]	Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus[J]. Curr Opin Endocrinol Diabetes Obes, 2017, 24: 73-79. doi: 10.1097/MED.0000000000000311 pmid: 27898586
[7]	Wortmann SB, Van Hove JLK, Derks TGJ, et al. Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor[J]. Blood, 2020, 136: 1033-1043. doi: 10.1182/blood.2019004465 pmid: 32294159
[8]	Grunert SC, Derks TGJ, Adrian K, et al. Efficacy and safety of empagliflozin in glycogen storage disease type Ib: data from an international questionnaire[J]. Genet Med, 2022, 24(8):1781-1788. doi: 10.1016/j.gim.2022.04.001 pmid: 35503103
[9]	梁翠丽, 刘丽, 盛慧英, 等. 糖原累积病Ib型患儿基因突变分析与临床研究[J]. 中国当代儿科杂志, 2013, 15: 661-665.
[10]	Sun Y, Hu G, Luo J, et al. Mutations in methionyl-tRNA synthetase gene in a Chinese family with interstitial lung and liver disease, postnatal growth failure and anemia[J]. J Hum Genet, 2017, 62: 647-651. doi: 10.1038/jhg.2017.10 pmid: 28148924
[11]	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17: 405-424. doi: 10.1038/gim.2015.30 pmid: 25741868
[12]	中华医学会儿科学分会消化学组, 中华医学会儿科学分会临床营养学组. 儿童炎症性肠病诊断和治疗专家共识[J]. 中华儿科杂志, 2019, 57(7): 501-507.
	中华医学会消化病学分会炎症性肠病学组. 中国消化内镜技术诊断与治疗炎症性肠病的专家指导意见[J]. 中华炎性肠病杂志, 2020, 4(4): 283-291.
[14]	中国医师协会儿科医师分会过敏学组, 中华医学会儿科学分会呼吸学组, 中国医师协会儿科医师分会风湿免疫学组, 等. 儿童反复呼吸道感染临床诊疗路径(2022版)[J]. 中国实用儿科杂志, 2022, 37(3):161-168.
[15]	Kubota M. Hyperuricemia in children and adolescents: present knowledge and future directions[J]. J Nutr Metab, 2019: 3480718.
[16]	Group WHOMGRS. WHO Child Growth Standards based on length/height, weight and age[J]. Acta Paediatr Suppl, 2006, 450: 76-85.
[17]	Van Limbergen J, Russell RK, Drummond HE, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease[J]. Gastroenterology, 2008, 135: 1114-1122. doi: 10.1053/j.gastro.2008.06.081 pmid: 18725221
[18]	Levine AP, Segal AW. What is wrong with granulocytes in inflantmatory bowel diseases?[J]. Dig Dis, 2013, 31: 321-327. doi: 10.1159/000354686 pmid: 24246982
[19]	Dicckgracfe BK, Korzenik JR, Husain A, et al. Association of glycogen storage disease lb and Crohn disecuse. results of a North American survey[J]. Eur J Peciatr, 2002, 161(Suppl 1): S88-S92.
[20]	Cai Z, Wang S, Li J. Treatment of inflammatory bowel disease: a comprehensive review[J]. Front Med (Lausanne), 2021, 8: 765474.
[21]	Gerin I, Veiga-da-Cunha M, Noel G, et al. Structure of the gene mutated in glycogen storage disease type Ib[J]. Gene, 1999, 227: 189-195. pmid: 10023055

患儿	父源			母源
患儿	核苷酸改变（NM_001164277）	氨基酸改变	ACMG评分	核苷酸改变（NM_001164277）	氨基酸改变	ACMG评分
P1	c.446G>A	p.G149E	P	c.446G>A	p.G149E	P
P2	c.446G>A	p.G149E	P	c.446G>A	p.G149E	P
P3	c.446G>A	p.G149E	P	c.446G>A	p.G149E	P
P4	c.357_358insC	p.C121MfsX10	P	c.446G>A	p.G149E	P
P5	c.2delT^1）	/	LP	c.1065delG^1）	p.S356VfsX47	LP

项目	初诊中位数	SGLT2抑制剂治疗前	SGLT2抑制剂治疗后	Z值	P
呼吸道感染/次·年^-1	6.0(2.0~12.0)	5.0(3.0~7.5)	3.0(1.0~4.0)	5.158	0.076
ALT/U·L^-1	132.0(92.5~389.0)	31.0(13.0~40.5)	29.0(12.0~39.0)	7.600	0.022
AST/ U·L^-1	386.0(139.5~1267.0)	26.0(16.5~28.5)	16.0(9.5~31.0)	8.400	0.015
GGT/ U·L^-1	370.0(56.5~535.5)	22.0(18.0~43.0)	23.0(16.0~36.5)	7.600	0.022
乳酸/mmol·L^-1	8.8(6.2~10.1)	3.1(1.8~3.7)	2.4(2.1~3.8)	7.600	0.022
尿酸SDS	3.53(－0.42~6.64)	2.04(－0.22~4.97)	－0.20(－0.68~1.37)	2.800	0.247
TG/mmol·L^-1	4.05(3.08~5.52)	2.27(1.41~3.64)	2.56(1.76~3.48)	7.429	0.024
TC/mmol·L^-1	4.82(2.95~5.74)	4.97(3.31~5.59)	3.79(3.64~5.70)	0.667	0.717
ANC×10⁹·L^-1	0.97(0.70~1.22)	0.75(0.40~1.69)	1.63(0.48~1.77)	1.600	0.449
Hb/g·L^-1	99.0(90.5~104.0)	99.0(87.5~116.0)	128.0(116.0~145.0)	8.400	0.015
身高SDS	－1.58(－2.11~0.03)	－2.39(－3.76~－2.30)	－2.14(－3.59~－1.50)	6.400	0.041
BMI SDS	0.49(－0.26~1.59)	0.23(－1.09~1.14)	0.20(－0.34~1.33)	0.400	0.819

项目	P1	P2	P3	P4	P5	M（P₂₅~P₇₅）
IBD发作年龄/岁	1.0	6.0	5.0	1.0	8.0	5.0(1.0~7.0)
行肠镜检查年龄/岁	6.8	13.0	6.3	6.0	17.0	6.8(6.2~15.0)
口腔溃疡发作年龄/岁	1.0	0.6	0.5	1.0	5.0	1.0(0.6~3.0)
腹痛发作年龄/岁	2.0	6.0	5.0	3.0	8.0	5.0(2.5~7.0)
腹泻发作年龄/岁	0.6	6.0	3.5	0.8	8.0	3.5(0.7~7.0)
肛周脓肿发作年龄/岁	0.6	10.0	6.0	1.0	10.0	6.0(0.8~10.0)
SGLT2抑制剂初剂量/mg·kg^-1·d^-1	0.2	0.16	0.16	0.36	0.22	0.20(0.16~0.29)
SGLT2抑制剂终剂量/mg·kg^-1·d^-1	0.5	0.31	0.39	0.28	0.29	0.31(0.29~0.45)
SGLT2抑制剂治疗时长/月	12	9	13	12	7	12.0(8.0~12.5)
SGLT2抑制剂治疗前PCDAI	65.0	35.0	60.0	45.0	55.0	55.0(40.0~62.5)
SGLT2抑制剂治疗后PCDAI	17.5	10.0	10.0	35.0	10.0	10.0(10.0~26.3)

合并炎症性肠病的糖原累积病-Ⅰb型5例患儿SGLT2抑制剂治疗效果分析

Therapeutic efficacy of an SGLT2 inhibitor in five pediatric patients with glycogen storage disease type Ⅰb and inflammatory bowel disease

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