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100023 北京市2345信箱	世界华人消化杂志 2001年6月15日;9(6):649-652
Email: wcjd@public.bta.net.cn	世界华人消化杂志 ISSN 1009-3079 CN 14-1260/R
http:// www.wjgnet.com	版权归世界胃肠病学杂志社

⊙研究原著⊙

大剂量维生素C对肝硬变患者肝功能及细胞免疫功能的影响

张晓岚姚希贤李永军王丽芳

河北医科大学第二医院消化内科河北省石家庄市 050000
张晓岚, 女, 1963-11-21生, 河北省涞源县人, 汉族. 1997年河北医科大学硕士，1999年河北医科大学博士生, 副主任医师, 副教授, 主要从事慢性肝病方面的研究, 发表论文13篇.
项目负责人 姚希贤，050000，河北省石家庄市，河北医科大学第二医院消化内科.
Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Correspondence to:Xiao Lan Zhang, Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Tel. 0086-311-7046901 Ext.8632
Email. zxl63@263.net
Received 2001-01-08 Accepted 2001-01-11

Effect of high-dose vitamin C on hepatic function and cell immunity in patients with liver cirrhosis

Zhang-Xiao Lan, Yao-Xi Xian, Li-Yong Jun and Wang-Li Fang

Abstract

AIM To observe the effects of high-dose vitamin C (Vit. C) on hepatic function and cell immunity in cirrhotic patients.

METHODS In the Vit. C-treated group, Vit. C (10g/day) was given intravenously. The plasma Vit. C levels were measured in 58 patients with cirrhosis by high performance liquid chromatography (HPLC). The levels of lymphocyte transformation test (LTT), T lymphocyte phenotype, and red blood cell C3b receptor rosette (RBC-C3bRR) as well as red blood cell immune complex rosette (RBC-ICR) were measured before and after vitamin C therapy.

RESULTS ① ALT and Bil were significantly decreased respectively (ALT: 1020±888nkΔt·L^-1 vs 516±422nkΔt·L^-1，P＜0.01; Bil: 47±42μmol·L^-1 vs 36±50μmol·L^-1，P＜0.05) after treatment with Vit. C. In control group, ALT was significantly decreased (700±583 nkΔt·L^-1 vs 1000±733 nkΔt·L^-1, P＜0.05); but Bil was unchanged after treatment. When compared with control group, both ALT and Bil were lower after treatment with Vit. C (P＜0.05). ② The CD4/CD8 ratio, lymphocyte transformation ratio and RBC-C3bRR were significantly higher than that before treatment in patients with cirrhosis respectively (1.08±0.28, vs 1.26%±0.24%; 46.70%±10.41%, vs 55.52%±7.83%; 20.37%±6.20%, vs 15.90%±7.11%), P＜0.01. And they were all lower than the normal (1.52%±0.29%, 59.14%±2.81%, 17.88%±3.30%, P＜0.05-0.01). ③ The Vit. C level of patients was positively correlated with CD4/CD8 ratio, LTT and RBC-C3bRR (r=0.613, 0.512, 0.567, P＜0.01).

CONCLUSION Vitamin C as a drug of protecting hepatic function plays an active role in patients with cirrhosis, and improves immunological function in cirrhotic patients.

Subject headings ascorbic acid/pharmacology; ascorbic acid/administration dosage; liver cirrhosis/drug therapy; liver cirrhosis/pathophysiology; immunity; cellular; randomized control test (RCT)

Zhang XL, Yao XX, Li YJ, Wang LF. Effect of high-dose vitamin C on hepatic function and cell immunity in patients with liver cirrhosis. Shijie Huaren Xiaohua Zazhi, 2001;9(6):649-652

摘要

目的观察大剂量维生素C(Vit.C)对肝硬变患者肝功能及细胞免疫功能的影响.

方法 Vit.C 10g稀释于50g·L^-1葡萄糖300mL～500mL中静脉点滴，1次·d^-1，连用14d～16d. 观察应用与未用Vit.C治疗的肝硬变患者共58例，治疗前后的ALT、胆红素(Bil)、血清Vit.C、淋巴细胞转化率、T淋巴细胞亚群、红细胞C3b受体花环率及红细胞免疫复合物花环率水平的变化.

结果治疗组应用Vit. C治疗后ALT（1020±888nkΔt·L^-1vs 516±422nkΔt·L^-1，P＜0.01）和Bil（47±42μmol·L^-1vs36±50μmol·L^-1，P＜0.05）明显降低；而且肝硬变Vit. C治疗组ALT（516±422 nkΔt·L^-1 vs 703±582nkΔt·L^-1，P＜0.05）和Bil（36±50μmol·L^-1 vs 48±56μmol·L^-1，P＜0.05）明显低于病例对照组. CD4/CD8比值、淋转率虽治疗前(1.08%±0.28%, 46.70%±10.41%)、后（1.26%±0.24%, 55.52%±7.83%)均仍明显低于正常(1.52%±0.29%)，P＜0.01；但治疗后明显高于治疗前，P＜0.05, P＜0.01. 红细胞C3b受体花环率治疗后(20.37%±6.20%)明显高于治疗前(15.90%±7.11%)，P＜0.05. 维生素C与CD4/CD8比值、淋转率、红细胞C3b受体花环率均呈正相关(n=31，r=0.613, 0.512, 0.567, P＜0.01).

结论大剂量维生素C静脉点滴在治疗肝硬变患者中，具有降酶退黄作用，是一种有效的临床护肝药物，其机制可能与提高细胞免疫和红细胞免疫粘附功能有一定关系.

主题词 抗坏血酸/药理学；抗坏血酸/投药和剂量；肝硬化/药物疗法；肝硬化/病理生理学；肝硬化/免疫学；免疫；细胞；随机对照试验

张晓岚, 姚希贤, 李永军, 王丽芳. 大剂量维生素C对肝硬变患者肝功能及细胞免疫功能的影响. 世界华人消化杂志，2001；9(6)：649-652

0 引言

慢性肝炎活动及肝细胞损害在临床上十分常见，尽管有许许多多药物用于护肝治疗^［^1-9^］，但尚乏特效疗法，有时颇感棘手. 自从维生素C（Vit. C）用于慢性肝病患者护肝治疗以来，有关本药对恢复肝功能、降酶、退黄作用，仅有少数体外或动物实验研究^［^10-20^］. 应用大剂量Vit. C（10g·d^-1）作为护肝药物以及对其作用机制的研究则少有报道^［^21-25^］. 为此，我们应用随机对照的方法，对58例肝硬变肝炎活动、肝功能损害患者采用大剂量 Vit. C静脉滴注，以观察其疗效. 同时对Vit. C与细胞免疫、红细胞免疫之间的关系进行了探讨.

1 材料和方法

1.1 材料 ①纳入标准：肝炎后肝硬变肝功能损害具有黄疸、和(或)转氨酶(ALT)增高达正常一倍以上；乙肝或丙肝病毒标志物阳性；实验室、B型超声、CT及其他辅助检查支持肝硬变诊断；部分肝炎后肝硬变经肝组织活检病理证实. ②排除标准：除外心、肾疾病、消化道溃疡、糖尿病以及消化道肿瘤等. 将符合上述标准的住院肝硬变患者58例，随机分为治疗组和对照组，治疗组31例，男24例，女7例，年龄24～75(50±13)岁，Child-Pugh A级8例，B级15例，C级8例. 病例对照组27例，男19例，女8例，年龄32～76(52±11)岁，A级6例，B级13例，C级8例. 两组在年龄、性别和Child-Pugh分级等方面均无显著性差别（P＞0.05，表1）. 健康家属、献血员、本院学生或工作人员30例为本研究的健康对照，其中男19例，女11例，年龄20～67(48±12)岁，其年龄、性别在统计学上与治疗组无显著性差别.

表1 肝硬变治疗组与病例对照组治疗前状况

	病例对照组	治疗组
n	27	31
男/女	19/8	24/7
年龄/岁	52±11	50±13
肝功能
A	6	8
B	13	15
C	8	8
Vit. C/mg/mL	0.023±0.010	0.024±0.007
ALT/nkΔt·L^-1	994±738	1020±888
Bil/μmol·L^-1	46±40	47±42

1.2 方法 两组肝硬变患者在相同支持疗法的基础上（如复合维生素B、肝太乐，腹水患者酌用安体舒通等利尿剂，必要时每周输入10g～20g的清蛋白）；治疗组加用Vit. C 10g（石家庄第一制药集团生产，批号9405271, 9605142），应用50g·L^-1葡萄糖300mL～500mL稀释后静脉滴注，1次·d^-1，连用14d，而后减量至5g再用2d停药. 所有病例均于治疗前和疗程结束后次日早晨空腹肘静脉采血，测定血浆清蛋白(A)，胆红素（Bil）、ALT、凝血酶原活动度(PTA)、靛青绿(ICG)排泄试验、血及胃液pH. 同时检测血清Vit. C水平，采用高效液相色谱（HPLC）分析法测定. 淋巴细胞转化率(lymphocyte transformation ratio, LTR)测定应用形态学（全血法），PHA培养瓶购自华美生物工程公司北京分公司. T淋巴细胞亚群（T lymphocyte phenotype，TLP）测定采用单克隆抗体碱性磷酸酶抗碱性磷酸酶（alkaline phosphatase anti-alkaline phosphatase，APAAP）法检测，药盒购自北京邦定生物医学公司. 红细胞C3b受体花环（RBC-C3Brr）及红细胞免疫复合物花环（RBC-CIR）试验采用郭峰法^［²⁶^］，致敏酵母菌和未致敏酵母菌试剂由河北医科大学微生物教研室提供.
统计学处理各项指标的测定结果均以x±s表示，组间均数差异性比较采用t检验、t＇检验、方差分析或秩和检验，治疗前后均数差异性比较采用配对资料的t检验，有关指标之间的相关关系采用直线相关分析. P＜0.05为有统计学意义.

2 结果

2.1 Vit. C对肝功能的影响 肝硬变Vit. C治疗组ALT（1020.04±888.18nkΔt·L^-1 vs 515.94±422.25nkΔt·L^-1，P＜0.01, P＜0.01）和Bil（46.81±41.96μmol·L^-1 vs 36.42±50.33μmol·L^-1, P＜0.05）明显降低. ② 病例对照组ALT也有下降（994.03±738.48 nkΔt·L^-1 vs 703.81±581.62 nkΔt·L^-1, P＜0.05），但对Bil无影响（P＞0.05）. ③ 肝硬变Vit.C治疗组ALT（30.95±25.33u vs 42.2±34.89u，P＜0.05）和Bil（36.42±50.33μmol·L^-1 vs 47.89±56.20μmol·L^-1，P＜0.05）明显低于病例对照组. ④ 两组对A，PTA，ICG均无显著性影响（P＞0.05）. 大剂量Vit. C对A级肝硬变患者能显著性降低ALT（P＜0.01)和Bil(25.67μmol·L^-1±18.36μmol·L^-1 vs 15.08μmol·L^-1±12.53μmol·L^-1，P＜0.05)的水平；对B级患者仅能降低ALT(60.73u±63.10u vs 27.20u±12.69u，P＜0.05)，对C级患者无明显影响（P＞0.05）.

2.2 Vit. C对免疫功能的影响 Vit. C能明显提高淋转率，CD4和CD4/CD8比值，治疗前后差异显著(P＜0.01，表2)，也明显提高RBC-C3b受体花环率（P＜0.05），降低RBC-IC花环率，但治疗前后比较无显著性差异（P＞0.05）. Vit. C与淋转率，CD4/CD8比值，RBC-C3b受体花环率均呈显著正相关(P＜0.01)，r值分别是0.512，0.613，0.567.

表2 Vit. C对免疫功能影响

	正常人	治疗前	治疗后
CD3(%)	58.92±8.26	49.18±9.16^b	52.56±8.94^e
CD4(%)	42.26±5.37	30.02±5.32^b	37.46±5.44^de
CD8(%)	30.18±6.02	35.57±9.64	33.87±13.84
CD4/CD8	1.52±0.29	1.06±0.26^b	1.26±0.24^de
LTR (%)	59.14±2.81	46.70±10.41^b	55.52±7.83^de
RBC-ICRR(%)	3.37±1.72	5.12±2.79^a	4.71±3.00
RBC-C3bRR(%)	17.88±3.30	15.90±7.11	20.37±6.20^c

^aP＜0.05, ^bP＜0.01, 治疗前 vs 正常人; ^cP＜0.05, ^dP＜0.01, 治疗前 vs 治疗后; eP＜0.05, 治疗后 vs 正常人.

3 讨论

实验研究表明，Vit. C对肝细胞具有保护作用^［^27-34^］：预先给予Vit. C能明显减低CCl₄诱发肝坏死引起的血糖、蛋白质的下降^［¹⁰^］；Vit. C能降低血清AST，ALT，LDH；组织学上Vit. C治疗组肝细胞坏死数量明显减少且坏死程度轻微^［¹¹^］，肝脏呈正常的棕红色；而未用Vit. C者呈苍白色；对D-半乳糖胺诱发的兔肝坏死和LEC兔^［¹²^］，Vit. C可改善肝炎症状，延缓黄疸出现，延长生存期. 上述表明，Vit. C对肝脏病变以及肝功能均具有保护作用. 本研究中大剂量Vit. C对肝硬变患者ALT和Bil有明显降低作用(P＜0.05～0.01)；与对照组比较，Vit. C组治疗后ALT，Bil下降均优于病例对照组；而且Vit. C疗效与肝功能状况明显相关，对A级患者能明显降低ALT和Bil，B级者仅能降低ALT，C级患者ALT，Bil虽也有下降，但乏统计学意义(P ＞0.05). 因此，对肝硬变ALT，Bil增高者，Vit. C大剂量(10g)疗法宜较早期进行，以达降酶、退黄的良好效果.肝硬变患者细胞免疫和红细胞免疫功能受损的观点已被反复证实^［^35-50^］. 研究表明，Vit. C具有提高机体免疫力作用：能提高淋巴细胞转化率，增强某些细胞介导免疫反应参数；能刺激IL1，IL6产生^［¹³^］；可提高CD₃，CD₄，CD₄/CD₈，降低CD₈^［⁵¹^］. 本研究中，肝硬变患者CD₄，CD₄/CD₈，淋转率均低于正常(P＜0.01)，RBC-ICR高于正常(P＜0.05). Vit. C治疗后CD₄，CD₄/CD₈，淋转率提高（P＜0.01），RBc-C3b受体花环率也提高（P＜0.05），RBc-ICR治疗前后变化无统计学意义. 我们也发现，Vit. C与CD₄/CD₈，淋转率，RBc-C3b受体花环率均呈正相关（r =0.613，0.512，0.567，P＜0.01). 以上资料表明肝硬变患者具有细胞免疫、红细胞免疫功能低下，Vit. C可提高细胞免疫和红细胞免疫粘附功能.
我们发现大剂量Vit. C治疗前后对血液和胃液pH值均无显著性变化(P＞0.05)，表明大剂量Vit. C静脉滴注不会对血液和胃液的酸碱度产生影响. 仅4例患者治疗过程中有轻微皮肤脱屑和痒感，停药后自行缓解，并无其他不良反应，表明大剂量Vit. C静脉点滴是有效、安全的降酶、退黄，改善肝功能疗法. 总之，我们认为大剂量Vit. C疗法确有降酶、退黄，改善肝功能的作用，且无毒副作用，是一种安全有效的护肝药物，提高细胞免疫和红细胞免疫粘附功能是其作用机制之一.

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