维生素D缺乏对非酒精性脂肪性肝炎患者FIB-4指数及病情严重程度的影响

周荃; 李金强; 黎晓武

doi:10.3969/j.issn.1001-5256.2022.06.015

维生素D缺乏对非酒精性脂肪性肝炎患者FIB-4指数及病情严重程度的影响

DOI: 10.3969/j.issn.1001-5256.2022.06.015

长沙市第一医院感染科，长沙 410000

基金项目:

长沙市科技局科研项目 (kq1907016)

伦理学声明：本研究方案于2019年7月1日经由长沙市第一医院伦理委员会审批，批号：20190613030，所纳入患者均签署知情同意书。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：周荃负责实施研究过程，采集整理数据，设计论文框架，起草论文，修订论文，终审论文；李金强负责调研整理文献，提出研究选题，设计研究方案；黎晓武负责统计分析，提供指导性支持。

详细信息

通信作者:
李金强，leejy2020@163.com

黎晓武，lxwdp@163.com

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出版历程
- 收稿日期: 2021-10-10
- 录用日期: 2021-11-12
- 出版日期: 2022-06-20

Influence of vitamin D deficiency on fibrosis-4 index and disease severity in patients with nonalcoholic steatohepatitis

Department of Infectious Diseases, The First Hospital of Changsha, Changsha 410000, China

Research funding:

Scientific Research Plan Project of the Science and Technology Bureau of Changsha (kq1907016)

More Information

Corresponding author: LI Jinqiang, leejy2020@163.com (ORCID:0000-0001-7403-1844); LI Xiaowu, lxwdp@163.com (ORCID:0000-0001-9913-1622)

摘要

摘要: 目的探讨维生素D缺乏对非酒精性脂肪性肝炎(NASH)的影响。方法选取2020年1月—2021年10月冬春季在长沙市第一医院感染科住院治疗的NASH患者，根据血清1, 25(OH)₂D₃水平分为3组：A组为1, 25(OH)₂D₃缺乏组(＜20 ng/mL)，B组为1, 25(OH)₂D₃不足组(20~30 ng/mL)，C组为1, 25(OH)₂D₃充足组(＞30 ng/mL)。比较3组患者血清1, 25(OH)₂D₃、ALT、AST、TBil、TC、TG、IL-18、IL-37水平和肝脏病理分级的差异，计算FIB-4指数。计量资料多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验。计数资料组间比较采用χ²检验。相关性采用Pearson相关分析。结果共纳入NASH患者120例，A、B、C 3组各40例。与A组比较，B、C两组患者1, 25(OH)₂D₃、IL-37水平升高，而FIB-4指数和ALT、AST、TBil、TC、TG、IL-18水平降低，差异均有统计学意义(P值均＜0.05)。与B组比较，C组患者1, 25(OH)₂D₃、IL-37水平升高，FIB-4指数和ALT、AST、TC、TG、IL-18水平降低，差异均有统计学意义(P值均＜0.05)。相关性分析结果显示，1, 25(OH)₂D₃与ALT(r=-0.84，P＜0.001)、AST(r=-0.77，P＜0.001)、TBil(r=-0.32，P＜0.001)、TC(r=-0.45，P＜0.001)、TG(r=-0.42，P＜0.001)、IL-18(r=-0.40，P＜0.001)及FIB-4指数(r=-0.62，P＜0.001)均呈负相关，而与IL-37(r=0.59，P＜0.001)呈正相关。与A组相比，B、C组中与重度脂肪变(χ²=51.46，P＜0.001)、桥接纤维化与早期肝硬化(χ²=36.59，P＜0.001)、桥接坏死与大片坏死(χ²=37.28，P＜0.001)比例下降。光镜示A组肝细胞广泛气球样变，大量大泡性为主的脂滴，肝板排列紊乱，淋巴细胞浸润，局灶桥接纤维化；B组多数为点灶坏死，门静脉周围纤维化，脂滴大小不等，少量中性粒细胞浸润，部分肝细胞气球样变；C组少量肝细胞气球样变，局灶窦周纤维化，少数点灶坏死，肝细胞胞质可见少量脂滴。结论维生素D水平越低，NASH患者肝损伤、肝纤维化程度越明显，检测维生素D有助于评估NASH患者病情进展情况。
- 非酒精性脂肪性肝病 /
- 维生素D /
- FIB-4指数 /
- 白细胞介素类
Abstract: Objective To investigate the influence of vitamin D deficiency on nonalcoholic steatohepatitis (NASH). Methods The patients with NASH who were hospitalized in Department of Infectious Diseases, The First Hospital of Changsha, from January 2020 to October 2021 were enrolled, and according to the serum level of 1, 25(OH)₂D₃, they were divided into group A with 1, 25(OH)₂D₃ deficiency (< 20 ng/mL), group B with 1, 25(OH)₂D₃ insufficiency (20-30 ng/mL), and group C with sufficient 1, 25(OH)₂D₃ (> 30 ng/mL). The three groups were compared in terms of the serum levels of 1, 25(OH)₂D₃, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), total cholesterol (TC), triglyceride (TG), interleukin-18 (IL-18), and interleukin-37 (IL-37) and liver pathological grade, and fibrosis-4 (FIB-4) index was calculated. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups; the chi-square test was used for comparison of categorical data between groups. A Pearson correlation analysis was also performed. Results A total of 120 NASH patients were enrolled, with 40 patients in each group. Compared with group A, groups B and C had significant increases in the levels of 1, 25(OH)₂D₃ and IL-37 and significant reductions in FIB-4 index and the levels of ALT, AST, TBil, TC, TG, and IL-18 (all P < 0.05). Compared with group B, group C had significant increases in the levels of 1, 25(OH)₂D₃ and IL-37 and significant reductions in FIB-4 index and the levels of ALT, AST, TC, TG, and IL-18 (all P < 0.05). The correlation analysis showed that 1, 25(OH)₂D₃ was negatively correlated with ALT (r=-0.84, P < 0.001), AST (r=-0.77, P < 0.001), TBil (r=-0.32, P < 0.001), TC (r=-0.45, P < 0.001), TG (r=-0.42, P < 0.001), IL-18 (r=-0.40, P < 0.001), and FIB-4 index (r=-0.62, P < 0.001), and it was positively correlated with IL-37 (r=0.59, P < 0.001). Compared with group A, groups B and C had significant reductions in the proportion of patients with severe steatosis (χ²=51.46, P < 0.001), bridging fibrosis and early liver cirrhosis (χ²=36.59, P < 0.001), or bridging necrosis and large-scale necrosis (χ²=37.28, P < 0.001). Light microscopy showed that group A had extensive ballooning degeneration of hepatocytes, a large number of lipid droplets (mainly macrovesicular lipid droplets), disordered arrangement of the liver plate, lymphocyte infiltration, and focal bridging fibrosis; group B mainly had spotted focal necrosis, periportal fibrosis, lipid droplets with various sizes, a small amount of neutrophil infiltration, and ballooning degeneration of some hepatocytes; group C had ballooning degeneration of a small number of hepatocytes, focal perisinusoidal fibrosis, a small number of lesions with spotted focal necrosis, and a small number of lipid droplets in the cytoplasm of hepatocytes. Conclusion The degree of liver injury and fibrosis increases with the reduction in vitamin D level, and vitamin D measurement helps to evaluate the progression of NASH.
- Non-alcoholic Fatty Liver Disease /
- Vitamin D /
- FIB-4 Index /
- Interleukins

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图 1 1, 25(OH)₂D₃与ALT、AST、TBil、TC、TG、IL-18、IL-37水平及FIB-4指数的相关性

Figure 1. Correlation between 1, 25(OH)₂D₃ and the levels of ALT, AST, TBil, TC, TG, IL-18, IL-37, FIB-4 index

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图 2 3组患者的肝脏病理组织学比较(HE染色，×4)

注：a，A组；b，B组；c，C组。

Figure 2. Liver histopathological comparison of the three groups (HE staining, ×4)

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表 1 3组患者观察指标比较

Table 1. Comparison of observation indexes of three groups

指标	A组 (n=40)	B组 (n=40)	C组 (n=40)	统计值	P值
男性[例(%)]	22(55.00)	21(52.50)	26(65.00)	χ²=3.45	0.178
年龄(岁)	41.35±7.33	38.30±12.57	40.10±9.96	F=1.30	0.275
1, 25(OH)₂D₃(ng/mL)	17.98±1.60	24.92±1.81¹⁾	33.21±2.74¹⁾²⁾	F=772.21	＜0.001
ALT(U/L)	81.72±10.13	55.44±13.48¹⁾	33.45±8.55¹⁾²⁾	F=333.35	＜0.001
AST(U/L)	73.20±15.27	44.40±10.68¹⁾	27.70±6.72¹⁾²⁾	F=323.76	＜0.001
TBil(μmol/L)	19.84±3.26	14.10±4.69¹⁾	13.42±4.91¹⁾	F=30.66	＜0.001
FIB-4指数	3.42±1.31	2.38±1.08¹⁾	1.40±0.62¹⁾²⁾	F=78.31	＜0.001
TC(mmol/L)	6.67±2.11	5.69±1.04¹⁾	4.71±1.09¹⁾²⁾	F=38.38	＜0.001
TG(mmol/L)	3.61±1.51	2.89±0.99¹⁾	2.12±1.01¹⁾²⁾	F=30.75	＜0.001
IL-18(ng/mL)	200.90±26.38	167.55±31.81¹⁾	148.23±33.63¹⁾²⁾	F=42.37	＜0.001
IL-37(ng/mL)	17.97±3.81	20.10±4.36¹⁾	24.96±3.31¹⁾²⁾	F=70.56	＜0.001
注：与A组比较，1)P＜0.05；与B组比较，2)P＜0.05。

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表 2 3组患者的肝脏病理组织学比较

Table 2. Comparison of liver histopathology among the three groups

肝脏病理组织学	A组 (n=40)	B组 (n=40)	C组 (n=40)	χ²值	P值
脂肪变分级[例(%)]				51.46	＜0.001
S0~S1	7(17.5)	27(67.5)	38(95.0)
S2~S3	33(82.5)	13(32.5)	2(5.0)
肝纤维化分期[例(%)]				36.59	＜0.001
F0~F2	14(35.0)	29(72.5)	39(97.5)
F3~F4	26(65.0)	11(27.5)	1(2.5)
炎症分期[例(%)]				37.28	＜0.001
H1~H2	6(15.0)	22(55.0)	32(80.0)
H3~H4	34(85.0)	18(45.0)	8(20.0)

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参考文献(28)

[1]	YOUNOSSI Z, ANSTEE QM, MARIETTI M, et al. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(1): 11-20. DOI: 10.1038/nrgastro.2017.109.
[2]	ESTES C, ANSTEE QM, ARIAS-LOSTE MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030[J]. J Hepatol, 2018, 69(4): 896-904. DOI: 10.1016/j.jhep.2018.05.036.
[3]	WATT MJ, MIOTTO PM, de NARDO W, et al. The liver as an endocrine organ-linking NAFLD and insulin resistance[J]. Endocr Rev, 2019, 40(5): 1367-1393. DOI: 10.1210/er.2019-00034.
[4]	TILG H, MOSCHEN AR, RODEN M. NAFLD and diabetes mellitus[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(1): 32-42. DOI: 10.1038/nrgastro.2016.147.
[5]	SANTHEKADUR PK, KUMAR DP, SANYAL AJ. Preclinical models of non-alcoholic fatty liver disease[J]. J Hepatol, 2018, 68(2): 230-237. DOI: 10.1016/j.jhep.2017.10.031.
[6]	GIL Á, PLAZA-DIAZ J, MESA MD. Vitamin D: Classic and novel actions[J]. Ann Nutr Metab, 2018, 72(2): 87-95. DOI: 10.1159/000486536.
[7]	CIEBIERA M, WŁODARCZYK M, CIEBIERA M, et al. Vitamin D and uterine fibroids-review of the literature and novel concepts[J]. Int J Mol Sci, 2018, 19(7): 2051. DOI: 10.3390/ijms19072051.
[8]	MARADANA MR, YEKOLLU SK, ZENG B, et al. Immunomodulatory liposomes targeting liver macrophages arrest progression of nonalcoholic steatohepatitis[J]. Metabolism, 2018, 78: 80-94. DOI: 10.1016/j.metabol.2017.09.002.
[9]	LIU XJ, WANG BW, ZHANG C, et al. Vitamin D deficiency attenuates high-fat diet-induced hyperinsulinemia and hepatic lipid accumulation in male mice[J]. Endocrinology, 2015, 156(6): 2103-2113. DOI: 10.1210/en.2014-2037.
[10]	ZHAN ZM, JIANG YQ, HU ZJ, et al. Relationship between serum IL-18 expression level and liver injury in children with fatty liver[J]. Exp Lab Med, 2017, 35(2): 274-275, 283. DOI: 10.3969/j.issn.1674-1129.2017.02.047. 詹忠明, 江永青, 胡志坚, 等. 儿童脂肪肝患者血清IL-18表达水平与肝损伤的关系[J]. 实验与检验医学, 2017, 35(2): 274-275, 283. DOI: 10.3969/j.issn.1674-1129.2017.02.047.
[11]	DENG J, ZHANG YH, DANG SS, et al. The change in the prevalence of fatty liver disease and related influencing factors among Karamay residents in 2009-2016 and related influencing factors[J]. J Clin Hepatol, 2021, 37(7): 1609-1613. DOI: 10.3969/j.issn.1001-5256.2021.07.026. 邓江, 张永红, 党双锁, 等. 克拉玛依市居民2009年-2016年脂肪性肝病患病率变化及影响因素分析[J]. 临床肝胆病杂志, 2021, 37(7): 1609-1613. DOI: 10.3969/j.issn.1001-5256.2021.07.026.
[12]	National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association; Fatty Liver Expert Committee, Chinese Medical Doctor Association. Guidelines of prevention and treatment for nonalcoholic fatty liver disease: A 2018 update[J]. J Clin Hepatol, 2018, 34(5): 947-957. DOI: 10.3969/j.issn.1001-5256.2018.05.007. 中华医学会肝病学分会脂肪肝和酒精性肝病学组, 中国医师协会脂肪性肝病专家委员会. 非酒精性脂肪性肝病防治指南(2018年更新版)[J]. 临床肝胆病杂志, 2018, 34(5): 947-957. DOI: 10.3969/j.issn.1001-5256.2018.05.007.
[13]	PLUDOWSKI P, HOLICK MF, GRANT WB, et al. Vitamin D supplementation guidelines[J]. J Steroid Biochem Mol Biol, 2018, 175: 125-135. DOI: 10.1016/j.jsbmb.2017.01.021.
[14]	KLEINER DE, BRUNT EM. Nonalcoholic fatty liver disease: Pathologic patterns and biopsy evaluation in clinical research[J]. Semin Liver Dis, 2012, 32(1): 3-13. DOI: 10.1055/s-0032-1306421.
[15]	ZHANG RC, WANG AZ. Experience in the application of diagnostic criteria for nonalcoholic fatty liver (Draft) (With pathological analysis of 30 cases)[J]. Mod Pract Med, 2002, 14(12): 657-658. DOI: 10.3969/j.issn.1671-0800.2002.12.015. 张荣春, 王爱忠. 《非酒精性脂肪肝诊断标准(草案)》应用的体会(附30例病理分析)[J]. 现代实用医学, 2002, 14(12): 657-658. DOI: 10.3969/j.issn.1671-0800.2002.12.015.
[16]	SIVELL C. Nonalcoholic fatty liver disease: A silent epidemic[J]. Gastroenterol Nurs, 2019, 42(5): 428-434. DOI: 10.1097/SGA.0000000000000443.
[17]	CHAKRAVARTHY MV, WADDELL T, BANERJEE R, et al. Nutrition and nonalcoholic fatty liver disease: Current perspectives[J]. Gastroenterol Clin North Am, 2020, 49(1): 63-94. DOI: 10.1016/j.gtc.2019.09.003.
[18]	YOUNOSSI Z, TACKE F, ARRESE M, et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[J]. Hepatology, 2019, 69(6): 2672-2682. DOI: 10.1002/hep.30251.
[19]	YEO SC, ONG WM, CHENG K, et al. Weight loss after bariatric surgery predicts an improvement in the non-alcoholic fatty liver disease (NAFLD) fibrosis score[J]. Obes Surg, 2019, 29(4): 1295-1300. DOI: 10.1007/s11695-018-03676-5.
[20]	WONG GL. Update of liver fibrosis and steatosis with transient elastography (Fibroscan)[J]. Gastroenterol Rep (Oxf), 2013, 1(1): 19-26. DOI: 10.1093/gastro/got007.
[21]	SACERDOTE A, DAVE P, LOKSHIN V, et al. Type 2 diabetes mellitus, insulin resistance, and vitamin D[J]. Curr Diab Rep, 2019, 19(10): 101. DOI: 10.1007/s11892-019-1201-y.
[22]	HU TP, TANG SD, YU ZB. Relationship between Vitamin D level in children and adolescents with nonalcoholic fatty liver disease: A Meta-analysis[J]. J Clin Hepatol, 2021, 37(3): 627-631. DOI: 10.3969/j.issn.1001-5256.2021.03.024. 胡庭鹏, 唐苏丹, 余泽波. 儿童和青少年非酒精性脂肪性肝病与维生素D水平关系的Meta分析[J]. 临床肝胆病杂志, 2021, 37(3): 627-631. DOI: 10.3969/j.issn.1001-5256.2021.03.024.
[23]	DABBAGHMANESH MH, DANAFAR F, ESHRAGHIAN A, et al. Vitamin D supplementation for the treatment of non-alcoholic fatty liver disease: A randomized double blind placebo controlled trial[J]. Diabetes Metab Syndr, 2018, 12(4): 513-517. DOI: 10.1016/j.dsx.2018.03.006.
[24]	GEIER A, EICHINGER M, STIRNIMANN G, et al. Treatment of non-alcoholic steatohepatitis patients with vitamin D: A double-blinded, randomized, placebo-controlled pilot study[J]. Scand J Gastroenterol, 2018, 53(9): 1114-1120. DOI: 10.1080/00365521.2018.1501091.
[25]	MARWAHA RK, YENAMANDRA VK, SREENIVAS V, et al. Regional and seasonal variations in ultraviolet B irradiation and vitamin D synthesis in India[J]. Osteoporos Int, 2016, 27(4): 1611-1617. DOI: 10.1007/s00198-015-3427-0.
[26]	SERRANO MA, CAÑADA J, MORENO JC, et al. Solar ultraviolet doses and vitamin D in a northern mid-latitude[J]. Sci Total Environ, 2017, 574: 744-750. DOI: 10.1016/j.scitotenv.2016.09.102.
[27]	HARRISON SA, GOODMAN Z, JABBAR A, et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis[J]. J Hepatol, 2020, 72(5): 816-827. DOI: 10.1016/j.jhep.2019.11.024.
[28]	SAKAI N, van SWERINGEN HL, BELIZAIRE RM, et al. Interleukin-37 reduces liver inflammatory injury via effects on hepatocytes and non-parenchymal cells[J]. J Gastroenterol Hepatol, 2012, 27(10): 1609-1616. DOI: 10.1111/j.1440-1746.2012.07187.x.