What is the clinical effectiveness of glutathione in the treatment of intrahepatic cholestasis in pregnancy?

 Intrahepatic cholestasis in pregnancy is a unique complication in the middle and late stages of pregnancy, which is mainly affected by family genetics, placental synthesis of estrogen and other factors during pregnancy, leading to a decrease in bile acids in the intestinal tract, which affects the body's absorption of vitamin K, resulting in a decrease in the synthesis of coagulation factors, which leads to a delay in the development of the fetus in the uterus, and then hypoxia, resulting in increased morbidity and mortality of fetuses [1~2]. This leads to delayed intrauterine development and hypoxia, resulting in increased fetal morbidity and mortality [1-2]. Adenosylmethionine butanedisulfonate is a physiologically active molecule present in human tissues and body fluids, which can participate in important biochemical reactions in the body as a methyl donor and precursor of physiological sulfhydryl compounds; Glutathione is a peptide containing sulfhydryl groups, which is a combination of glutamic acid, cysteine, and glycine, and it has good antioxidant effects, can effectively play the integrative and detoxification effects, and can effectively maintain the normal immune function of the patient's body. It can also effectively maintain the normal immune function of patients, and is often used as an important reducing agent in clinical practice[3~4] . In this study, 64 patients with intrahepatic cholestasis in pregnancy admitted to our hospital were selected as research subjects to study the effect of glutathione combined with adenosylmethionine butanedisulfonate in the treatment of intrahepatic cholestasis in pregnancy. The results are reported as follows:

 

1 Information and methodology

1.1 General information    

Sixty-four patients with intrahepatic cholestasis in pregnancy admitted to our hospital from June 2019 to June 2021 were divided into single-medication group and combined-medication group according to randomized numerical table method, each with 32 cases. In the single-medication group, ages ranged from 23 to 48 years, with a mean of 35.67±3.57 years; gestational weeks ranged from 26 to 35 weeks, with a mean of 30.12±1.11 weeks. In the combination group, age ranged from 23 to 48 years, with a mean of (35.51±3.55) years; gestational weeks ranged from 26 to 35 weeks, with a mean of (29.96±1.08) weeks. There was no significant difference between the baseline data of the two groups (P>0.05). This study was approved by the Medical Ethics Committee of the hospital.

 

1.2 Inclusion and exclusion criteria    

Inclusion criteria: intrahepatic cholestasis in pregnancy as determined by serum bile acids or liver function tests; no significant allergy to study medications; voluntary participation in the study. Exclusion Criteria: malignant tumors, gestational diabetes mellitus, hypertension, communication disorders, systemic diseases.

 

1.3 Treatment   

 In the single-administration group, adenosylmethionine butanedisulfonate (China National Drug Code H20203260) was used for treatment. In the single-administration group, glutathione (NDT H20030002) was used in addition to the single-administration group. 2.4 g of glutathione (NDT H20030002) was dissolved in 500 ml of 0.9% sodium chloride solution and given intravenously once a day. 2.4 g of glutathione was dissolved in 500 ml of 0.9% sodium chloride solution for intravenous drip, once /d. Both groups continued treatment for 4 weeks. If amniotic fluid or intrauterine distress occurs, the pregnancy should be terminated promptly.

 

1.4 Criteria for assessing efficacy    

Apparent effect: after 4 weeks of treatment, patients' clinical symptoms disappear, bile acid basically recovered, liver function basically recovered; Effective: after 4 weeks of treatment, patients' clinical symptoms improved, bile acid not more than 1 times the normal level, liver function gradually improved; Ineffective: after 4 weeks of treatment, patients' clinical symptoms not improved, bile acid more than 1 times the normal level.

 

1.5 Observation indicators  

(1) Efficacy of treatment. (2) Liver function, recording the levels of bile acid (TBA), alanine aminotransferase (ALT), and azelaic transaminase (AST) before and after treatment. Fasting venous blood was collected from patients before and after treatment, and tested by automatic biochemical analyzer (Hitachi). (3) The degree of itching was recorded before and after the treatment. The degree of itching was scored according to the criteria for scoring the degree of itching in the Guidelines for the Diagnosis and Treatment of Intrahepatic Cholestasis in Pregnancy, and a 4-point scale was used, with a score of 0 indicating no itching, a score of 1 indicating occasional itching, a score of 2 indicating occasional itching, a score of 3 indicating occasional itching accompanied by symptoms, and a score of 4 indicating continuous itching. (4) Lipid peroxidation levels, glutathione (GSH) and malondialdehyde (MDA) levels were recorded before and after treatment in both groups. Fasting venous blood was taken before and after treatment, and the kit (Nanjing Jianjian Bioengineering) was used for detection. (5) Adverse pregnancy outcomes.

 

1.6 Statistical methods    

SPSS22.0 software was used to analyze the data. Measurement data were expressed as (x ± s) and t-test was used; count data were expressed as % and χ2 test was used. The test level was α=0.05, and P<0.05 was regarded as statistically significant.

 

2 Results

2.1 Comparison of therapeutic efficacy between the two groups The total effective rate of the combination group was 96.88%, higher than that of the single-medication group (75.00%). See Table 1.

 

2.2 Comparison of liver function indexes between the two groups    

The levels of AST, ALT and TBA in the combination group were lower than those in the single-drug group after treatment (P < 0.05). See Table 2.

 

2.3 Comparison of itchiness scores between the two groups    

Itching scores were lower in the combination group than in the single-agent group after treatment (P < 0.05). See Table 3.

 

2.4 Comparison of adverse pregnancy outcomes between the two groups    

The incidence of fetal asphyxia in the combination group was 3.12%, which was lower than that of 25.00% in the single-medication group (P<0.05); the incidence of postpartum hemorrhage and amniotic fluid contamination in the combination group was 9.38% and 3.12%, which were statistically insignificant when compared with those of the single-medication group, which were 18.75% and 3.12%, respectively (P>0.05). See Table 4.

 

2.5 Comparison of lipid peroxide levels between the two groups    

GSH and MDA levels were lower in the combination group than in the single-drug group after treatment (P < 0.05). See Table 5.

 

3 Discussion

Intrahepatic cholestasis in pregnancy is associated with sudden and unpredictable fetal death, and the risk is related to the severity of the disease, with significant geographic and racial disparities, and is associated with drug use, environmental changes, and elevated estrogens, and is characterized by itching, insomnia, fatigue, and loss of appetite. Intrahepatic cholestasis in pregnancy will lead to a decrease in energy supply, which will lead to abnormal bile acid metabolism, increase cholesterol and phospholipids in the patient's cells and tissues, which will seriously jeopardize the permeability of the patient's bile acid, and also lead to changes in protein synthesis of the hepatocytes, which will lead to an increase in the reflux of bile, and strengthen the toxicity of the bile acid in the body of the patient, which is detrimental to the patient's fetus, and will cause fetal deaths. The disease also causes changes in the synthesis of liver cell proteins. This disease also causes coagulation disorders in patients, resulting in postpartum hemorrhage, seriously endangering the life and health of patients and decreasing the survival rate of the fetus [5-6].

 

Adenosylmethionine butanedisulfonate methylates plasma membrane phospholipids and improves circulation in the liver, thereby utilizing transsulfuration changes. Its main function is to supplement adenosylmethionine, which can accelerate the metabolism and synthesis of sulfide products in the detoxification process, and is mainly used in the treatment of hepatobiliary diseases. Adenosylmethionine butanedisulfonate can improve the fluidity of hepatocytes, effectively enhance the activity of corresponding enzymes, promote the secretion and operation of bile, and also effectively participate in the synthesis of neurotransmitters, thus reducing the damage of toxic substances to the liver. Glutathione, as a major substance to improve metabolic synthesis in cells, is a kind of antioxidant, which can strengthen the antioxidant function of living organisms, maintain normal immune function, and effectively eliminate the destruction of the membrane structure of red blood cells by oxidizing agents, so as to participate in a variety of redox reactions of the patient's organism. Glutathione can also be added to various biochemical reactions in the human body, resulting in the acceleration of the synthesis and metabolism of sugars, fats and proteins, assisting in the elimination of oxygen free radicals and peroxides, so as to maintain the stability of the patient's organism, and activating the sulfhydryl enzymes in the body of the patient, effectively promoting the metabolism of proteins and fats, and improving the metabolic function of the patient. Glutathione can also effectively reduce the toxicity of toxic substances, clean up the body of the patient's toxic substances, is a very broad-spectrum detoxification of important substances, has a good effect on growth promotion, and thus promote the rapid recovery of the patient [7~8].

 

According to the results of this study, the total effective rate of the combination group was 96.88%, which was higher than that of the single-drug group (75.00%) (P＜0.05), suggesting that the combination of the two drugs can enhance the therapeutic effect. The reason for this is that the combination of the two drugs can effectively exert synergistic effects, exert pharmacological effects similar to those of coenzymes, further stimulate the body's mercapturial enzymes, thus promoting the metabolism of proteins and fats in patients, and can also participate in the methylesterification of cellular phospholipids, promoting the synthesis of membrane phospholipids, restoring the fluidity of membranes, and facilitating patients' recovery as soon as possible, thus enhancing the therapeutic effects of patients[9~10] . Further studies showed that compared with the single-agent group, the levels of AST, ALT, and TBA were lower in the combination group after treatment (P<0.05), suggesting that the combination of the two drugs can regulate liver function. The reason for this is that the combination of the two drugs can play the role of hormone inactivation and detoxification, and can also effectively promote bile acid metabolism, further improve the digestion and absorption of cellulose, and the combination of the two drugs can effectively protect the liver, promote the production of endogenous sulfhydryl groups, and further strengthen the levels of glutathione and cysteine, which can restore the damaged liver cells, and also effectively reduce the harm of toxins to the hepatocytes to further achieve the purpose of regulating liver function. It can also effectively reduce the damage of toxins to hepatocytes, and further achieve the purpose of regulating liver function. The data of this study also showed that compared with the single-agent group, the itchiness score was lower in the combination group (P<0.05), suggesting that the combination of the two drugs could reduce the itching symptoms. The reason for this is that the combination of the two drugs can alleviate the itching symptoms of patients and relieve their pain, and the combined effect of the two drugs can inhibit the activity of catecholamines and estrogen, prevent the stimulation of bile salts and bile by estrogen to avoid the occurrence of various adverse reactions, and promote the improvement of the symptoms of patients[11-12] .

 

Compared with the single-drug group, GSH and MDA levels were lower in the combination group after treatment (P＜0.05), suggesting that the combination of the two drugs can reduce the content of lipid peroxides. The reason is that MDA is the most important product of peroxidation of polyunsaturated fatty acids in membrane lipids, which can directly reflect the level of oxygen free radicals; GSH is an important antioxidant and oxygen free radical scavenger in the human body. GSH is an important antioxidant and oxygen free radical scavenger in human body. The combination of the two can enhance the activity of GSH and MDA to remove the excessive oxygen free radicals in the patient's body, improve the scavenging ability of the organism to oxygen free radicals, and can also effectively prevent the damage formed by lipid peroxidation and oxygen free radicals, improve the cerebral circulation of the patient, and effectively resist the damage caused by oxidation of the organism. The incidence of fetal asphyxia in the combined group was 3.12%, lower than the 25.00% in the single-administration group (P＜0.05), and the incidence of postpartum hemorrhage and amniotic fluid contamination in the combined group was 9.38% and 3.12%, which were not significantly different from that in the single-administration group (P＞0.05), suggesting that combining the two drugs can reduce the adverse pregnancy outcomes. The reason is that the combination of the two drugs can protect the liver, promote the synthesis of endogenous sulfhydryl groups, effectively contract and regulate the smooth muscle of the uterus, further improve the microcirculation abnormality, which is conducive to promoting the growth and development of the fetus and increasing the probability of fetal survival, and also effectively improve the damage to the endothelial cells of the vasculature, which can effectively enhance the volume of amniotic fluid while strengthening the perfusion of the placenta and preventing recurrence of microcirculation anomalies. It can effectively improve the outcome of pregnancy.

 

In conclusion, glutathione combined with adenosylmethionine butanedisulfonate can enhance the therapeutic efficacy of patients with intrahepatic cholestasis in pregnancy, improve liver function and itching symptoms, and reduce the level of lipid peroxides, with good safety.

 

References:

[1] ZHAO Bingfeng, CHEN Ran, HUANG Xuegui, et al. Effect of pharmacologic monitoring model in patients with intrahepatic cholestasis during pregnancy[J]. Journal of Clinical Reasonable Medication,2021,14(18):160-162,165.

[2] LI Guixiang, LIU Lingling, MAO Yufang, et al. Effects of adenosylmethionine butanedisulfonate combined with dexamethasone on liver function and serum TNF-α and IL-12 levels in patients with intrahepatic cholestasis during pregnancy[J]. Modern Biomedical Progress,2017,17(19):3765-3768.

[3] FANG Fang, PAN Dan, CAI Junbo. Effect of polyenophosphatidylcholine combined with glutathione in the treatment of intrahepatic cholestasis in pregnancy and its impact on perinatal outcome[J]. China Modern Physician,2020,58(2):16-19.

[4] PAN Juelong, MONG Wenxia, YE Yunfei. Effect of glutathione combined with adenosylmethionine butanedisulfonate in the treatment of intrahepatic cholestasis during pregnancy[J]. China Medicine Herald,2019,16(9):90-93.

[5] CHEN Zhi-Min, NIU Yang, LIU Xiao, et al. Clinical study of ursodeoxycholic acid combined with low molecular heparin calcium injection and adenosylmethionine butanedisulfonate in the treatment of intrahepatic cholestasis in pregnancy[J]. International Journal of Obstetrics and Gynecology,2017,44(6):642-646.

[6] QIN Li, ZHANG Jingjing, FU Kai'e, et al. Observations on the efficacy of polyenophosphatidylcholine combined with adenosylmethionine butanedisulfonate in the treatment of intrahepatic cholestasis in pregnancy[J]. Liver,2019,24(11):1326-1328.

[7] Wu Xiaoxi. Effect of Yin gardenia Huang granules combined with glutathione on pregnancy ending and liver function in patients with cholestasis in pregnancy[J]. China Medical Engineering,2019,27(1):76-78.

[8] Hai Chang'e. Effect of Jin Yin Huayu Formula combined with adenosylmethionine butanedisulfonate on liver enzymes and lipid peroxidation in intrahepatic cholestasis during pregnancy[J]. Chinese Journal of Traditional Chinese Medicine,2019,37(3): 734-737.

[9] PENG Qiongyu, ZHANG Zhiping, LIU Jinyang. Observation on the effect of glutathione combined with adenosylmethionine butanedisulfonate in the treatment of intrahepatic cholestasis during pregnancy[J]. China Journal of Practical Medicine,2020,47(1):112-114.

[10] ZHOU Huiren, ZHAO Junqing, LI Yujing. Effect of glutathione combined with adenosylmethionine butanedisulfonate in the treatment of intrahepatic cholestasis in pregnancy[J]. Clinical Medicine,2020,40(1):91-92.

[11] Zhang Liyan. Feasibility of adenosylmethionine-assisted treatment of intrahepatic cholestasis in pregnancy and its effect on liver function[J]. Clinical Research,2019,27(6):115-116.

[12] LI Dongbei, LIN Hualan, ZENG Juhuan. Efficacy of ursodeoxycholic acid combined with glutathione in the treatment of intrahepatic cholestasis in pregnancy and its effect on hepatobiliary function[J]. Medical Theory and Practice,2021,34(7):1191-1192.