Intrahepatic cholestasis of pregnancy

　　Although many scholars have been committed to the study of the pathogenesis of ICP in the past 20 years, the exact pathogenesis is still not fully clear. Based on a large number of epidemiological surveys, clinical observations, and experimental research, it can be considered that the onset of ICP is closely related to estrogen and genetics. There are many clinical manifestations suggesting that excessive estrogen levels may be a cause of ICP, according to the epidemiological perspective. ICP often occurs in the late pregnancy period, which is the peak period of estrogen secretion; its incidence is significantly higher in twins than in singletons, about 5 to 6 times; the manifestations of cholestasis in women using contraceptives containing estrogen and progesterone are very similar to the symptoms of ICP during pregnancy; the recurrence rate of ICP in women who have had ICP during pregnancy is higher than usual when they become pregnant again.

　　1. The relationship between estrogen and intrahepatic cholestasis of pregnancy

　　(1) Clinical basis: There are many clinical manifestations suggesting that excessive estrogen levels may be a cause of intrahepatic cholestasis of pregnancy (ICP). The following are listed: ① ICP often occurs in the late pregnancy period, which is the peak period of estrogen secretion; ② The incidence of ICP in twins is significantly higher than that in singletons. The Shanghai Sixth People's Hospital reported that the incidence of ICP in twins is 6 times higher than that in singletons, which may be related to the significantly larger placental volume in twins and the higher estrogen secretion compared to singletons; ③ The manifestations of cholestasis in women using contraceptives containing estrogen and progesterone are very similar to the symptoms of ICP during pregnancy; ④ The recurrence rate of ICP in women who have had ICP during pregnancy is higher than usual when they become pregnant again.

　　(2) Laboratory research: Many scholars have used animal studies to investigate the effect of estrogens on bile secretion. It is believed that estrogens can cause bile stasis through the following pathways: ① Increased permeability of bile; ② Decreased activity of sodium-potassium ATPase (Na-K-ATPase) in the sinusoidal space area, which hinders the transport of bile salts; ③ Decreased fluidity of the cell membrane in the sinusoidal space area, which causes obstacles in the passage of bile salts; ④ Estrogen metabolites: D-glucuronide estrogens, which are structurally similar to bile acids, become competitive inhibitors of bile acid carriers. The large amount of estrogens produced during pregnancy can lead to bile stasis in some pregnant women; ⑤ Estrogen receptors in the liver and protein synthesis: It is speculated that estrogens can reduce the synthesis of organic anions and bile acid carriers, and also affect the translocation of organic anions bound to intracellular proteins, the movement of secretory vesicles to the bile duct area, and so on.

　　The relationship between intrahepatic cholestasis of pregnancy and pregnancy hormones

　　Pregnancy hormone is also a hormone secreted by the placenta. Although humans usually have good tolerance to pregnancy hormones, recent clinical observations and experiments have found that there is also a relationship between pregnancy hormones and the onset of intrahepatic cholestasis of pregnancy. Bacq et al. (1998) studied 13 patients with intrahepatic cholestasis of pregnancy, of whom 10 had received treatment with pregnancy hormones (0.2-1.0g/d) before developing intrahepatic cholestasis of pregnancy, and some patients recovered naturally after stopping the medication. However, little is known about the mechanism of intrahepatic cholestasis caused by progesterone. Early research suggested that the mechanism of bile stasis caused by pregnancy hormones during pregnancy is similar to that of estrogens. Meug et al. (1997) simultaneously measured bile acids and progesterone metabolites in the blood and urine of pregnant women with intrahepatic cholestasis of pregnancy and normal pregnant women. The results showed that the sulfated products of 5β-pregnan-3α, 20α-diol in the blood of pregnant women with intrahepatic cholestasis of pregnancy during pregnancy increased, while the products of conjugated progesterone with glucuronic acid did not change or even decrease. The main metabolites of progesterone in the blood are excreted through bile, about 30% of which are sulfated in combination with pyrosulfate, and may be transported by organic anion carriers. The increase in pyrosulfate of progesterone in the blood of patients with intrahepatic cholestasis of pregnancy during pregnancy may reflect impaired biliary secretion function, but glucuronic acid does not change, indicating that patients with intrahepatic cholestasis of pregnancy have a selective defect in the secretion of sulfated steroid compounds in the bile duct. Ding Xilai et al. (2001) conducted animal experiments using pregnant rats, injecting progesterone at a dose of 150mg/kg daily from the 13th day of pregnancy to the 20th day. The results showed that in addition to the increase in liver enzymes, bile acids, and bilirubin in the serum, there were dilated capillaries visible under the electron microscope with high electron density deposits inside. The results gave the pregnant rats the biochemical manifestations of estrogen, with similar pathological changes in the liver. Under electron microscopy, the changes were more similar to those in human intrahepatic cholestasis of pregnancy. Therefore, pregnancy hormones may also be a cause of intrahepatic cholestasis of pregnancy, but its true mechanism still needs further research at the molecular biological level.

　　3. The relationship between intrahepatic cholestasis of pregnancy and anticardiolipin antibody

　　Anticardiolipin antibody (ACA) is an autoimmune antibody, which is an important manifestation of autoimmune abnormalities. The target antigen of ACA is located on the endothelial cells of blood vessels and platelet membranes. ACA acts on the target site, damaging the endothelial cells of blood vessels, resulting in a decrease in the synthesis of prostaglandin I2 (PGI2); at the same time, it activates platelets, causing platelet adhesion, aggregation, and the release of thromboxane A2 (TXA2). The pathophysiological basis for adverse pregnancy outcomes in patients with positive ACA is mainly the pathological basis of villous vascular lesions and widespread thrombosis and infarction in the placental vessels. The level of circulating ACA in patients with intrahepatic cholestasis of pregnancy is significantly elevated, suggesting that there may be some connection between the two. Observing from the aspects of decreased blood rheology, abnormal lipid metabolism, and increased serum laminin (related to basement membrane damage), intrahepatic cholestasis of pregnancy has some similar changes with preeclampsia. Therefore, some scholars believe that immune dysfunction and autoimmune imbalance may also be one of the common pathophysiological changes related to the onset of both diseases, and the liver cells may also be attacked by ACA, leading to delayed liver blood flow, liver cell dysfunction, and the occurrence of intrahepatic cholestasis. These issues require further study.

　　4. The relationship between selenium and intrahepatic cholestasis of pregnancy

　　Selenium (selenium, Se) is a trace element. During pregnancy, to meet the needs of the mother, the intake of Se increases. Se is an active component of glutathione peroxidase, and its function is believed to be related to vitamin E. From epidemiological observations, the incidence of ICP during pregnancy seems to have seasonal variations. Reyes et al. (2000) measured the concentration of selenium in the blood, and compared with 9 years ago, the level of Se in non-pregnant women increased from (0.85±0.13) μmol/L to (1.43±0.34) μmol/L, and decreased to (1.08±0.25) μmol/L in the late pregnancy. To study its seasonal relationship, Reyes et al. tried to investigate the changes in the blood levels of Se, Zn, and Cu in pregnant women in different seasons. The results showed that the blood level of Se was as high as (1.34±0.19) μmol/L in summer, while Zn and Cu decreased. Reyes et al. believe that the decrease in the incidence of ICP in recent years may be related to the increase in Se, and the decrease in the incidence in summer may be related to the blood level of selenium in summer. In China, Wang Zhuchen et al. (2000) also studied the level of selenium in the blood of patients with ICP, the level of selenium in the placenta, and its relationship with glutathione peroxidase. The levels of selenium in the blood and placenta of patients with ICP were lower than those of normal individuals, and the activity of glutathione peroxidase also decreased, showing consistency. During normal pregnancy, antioxidant action can prevent oxidative damage to estrogen. However, when the activity of glutathione peroxidase decreases in patients with ICP, the cell antioxidant defense ability decreases, and the load of estrogen increases, leading to the formation of free radicals, affecting the cell membrane of the liver, and reducing the ability to excrete bile.

　　1. Preterm Delivery

　　In 1966, Haemmerli reported 18 cases of intrahepatic cholestasis of pregnancy (ICP) with a total of 43 pregnancies, 23 of which ended in preterm delivery, with 22 preterm deliveries concentrated in 8 patients. In 1976, Reid reported 56 cases of ICP, with 18 preterm deliveries among the 50 live births, resulting in a preterm delivery rate of 36%, and the weight was mentioned.

　　2. Fetal Distress

　　In 56 cases reported by Reid (1976), there were 6 stillbirths, with a perinatal mortality rate of 11%, 5 cases of cesarean section due to cephalopelvic disproportion among the 50 live births, and in the remaining 45 cases, 12 cases (27%) had severe amniotic fluid contamination, and the fetal heart rate was mentioned.

　　The cause of fetal distress has not been clarified yet. Laatikainen (1977) studied the relationship between fetal serum bile acid levels in pregnant women with intrapartum cholestasis of pregnancy and fetal distress. Among 41 cases of intrapartum cholestasis of pregnancy (1 case of twins), 16 cases showed signs of fetal distress. The umbilical cord blood CA level in the fetus with intrapartum cholestasis of pregnancy was 3.74μg/ml, while the umbilical cord blood CA level in the normal control group was only 0.94μg/ml. Among the 22 cases with umbilical cord blood CA levels above 3.74μg/ml, 12 had fetal distress, and among the 20 cases with umbilical cord blood CA levels below 3.74μg/ml, only 4 had fetal distress. Animal experiments also prove that if bile acids are administered orally or intravenously, they can cause liver cell damage. Therefore, Laatikainen believed that the occurrence of intrapartum cholestasis of pregnancy in the mother leads to an increase in CA in the fetus, which has an adverse effect on the fetus. Changes in the metabolism of fetal steroid substances can also lead to fetal distress. In 1991, Sepulveda reported that the effect of different concentrations of CA on free villous veins was found to be related, that is, there is a significant vasoconstriction at high concentrations. Therefore, in severe intrapartum cholestasis of pregnancy with hyperbilirubinemia, the vasoconstriction can increase resistance, reduce blood flow, and decrease oxygen exchange capacity, leading to intrauterine fetal distress.

　　In recent years, it is believed that the fetal distress in patients with intrapartum cholestasis of pregnancy is related to the shrinkage of the intervilous space. In 1980, Costoya and others observed that the placenta of patients with intrapartum cholestasis of pregnancy showed an increase in syncytiotrophoblasts, sparse and edematous villous matrix, thickened syncytiotrophoblastic layer, and a significant increase in cell trophoblast cells. Costoya believed that regardless of whether these changes are primary or secondary, as the result of these lesions is the narrowing of the intervilous space, the maternal blood flow in the intervilous space per unit time decreases, leading to fetal hypoxia. In 1987, Liu Boning and others conducted histometric analysis on 20 placentas of patients with intrapartum cholestasis of pregnancy to determine multiple parameters, and used 20 placentas of normal pregnant women of the same gestational age as controls. It was found that the intervilous space in the group with intrapartum cholestasis of pregnancy was significantly smaller than that in the normal control group, P0.1. Therefore, it can be considered that the narrow intervilous space may also be an important reason for the increased perinatal mortality rate in patients with intrapartum cholestasis of pregnancy.

　　3. Postpartum hemorrhage

　　Reid (1976) reported that among 50 cases of intrapartum cholestasis of pregnancy delivered vaginally, 10 cases had bleeding over 500ml, among which 5 cases had over 2000ml; and Frielaender also had the same report. In 1988, Hou Lirong and others observed postpartum hemorrhage in 158 cases of intrapartum cholestasis of pregnancy and compared them with 158 normal parturients with the same obstetric conditions. The average bleeding volume at 24 hours postpartum in the two groups was 234ml and 177.1ml, respectively, with a significant difference. Reid believed that the insufficient placental secretion of bile in pregnant women with intrapartum cholestasis of pregnancy, reduced absorption of vitamin K, and decreased synthesis of coagulation factors II, VII, IX, and X in the liver lead to postpartum hemorrhage.

　　4. Obstetric complications

　　(1) ICP associated with pregnancy-induced hypertension (PIH): In 1987, Dai Zhongying found that 24% of 250 cases of ICP during pregnancy were associated with PIH. Subsequently, Huang Yajuan summarized that among 10,243 deliveries from 1986 to 1994, there were 451 cases (4.4%) of ICP during pregnancy, 901 cases (8.8%) of PIH, and 79 cases (0.77%) with coexistence of ICP during pregnancy and PIH. The incidence of PIH in the ICP group was 17.52%, and the incidence of ICP in the PIH group was 8.72%, which were both significantly higher than the incidence in the general population. The perinatal mortality rates of the three groups of ICP, PIH, and ICP associated with PIH were 18.81%, 13.30%, and 59.52%, respectively, with the latter being significantly higher than the former. Therefore, for pregnant women with ICP complicated by PIH, more active management should be considered, including strengthening fetal monitoring, promoting fetal lung maturation, and timely termination of pregnancy.

　　(2) Intrahepatic cholestasis of pregnancy (ICP) associated with multiple pregnancies: In 1987, Dai Zhongying summarized 250 cases of ICP during pregnancy and noticed that there were 5 cases of twins. In 1989, Gouzale reported that 20.9% of 62 twin pregnancies were associated with ICP during pregnancy, which is extremely significant compared to the 4.7% incidence of ICP in singleton pregnancies. In the quantitative determination of urinary estriol (E3) in both groups, twins showed a significant increase compared to singletons, although it did not reach a statistically significant level. However, it can explain the role of estrogen in the formation of ICP during pregnancy. In 1997, Tao Minfang et al. reported that among 12,886 deliveries, there were 90 twin pregnancies (7‰). Among the 80 twin pregnancies with complete data, 24 cases (30%) were associated with ICP during pregnancy. Compared to 540 cases (4.2%) of ICP during pregnancy among 12,796 singleton deliveries, there was a significant difference in incidence. The gestational age of twins with and without ICP during pregnancy was 34+3 weeks and 36+1 weeks, respectively, and the incidence of pregnancy-induced hypertension was 54.2% and 33.9%, respectively, and the incidence of postpartum hemorrhage was 37.5% and 16.1%, respectively. The differences were all statistically significant.

　　Intrahepatic cholestasis of pregnancy may appear with itching during the second or third trimester of pregnancy, or itching may coexist with jaundice, which disappears rapidly after delivery.

　　Itching is often the first symptom to appear, usually starting between 28 to 32 weeks of gestation, but there are also cases as early as 12 weeks of pregnancy. In the 250 cases reported by Dai Zhongying, excluding 6.4% whose onset time was unknown, itching started in early pregnancy (before 12 weeks of pregnancy), mid-pregnancy (1-2 weeks), and late pregnancy (28-40 weeks), accounting for 1.2%, 23.2%, and 69.2% respectively. The degree of itching also varies, ranging from mild and occasional to severe generalized itching, with some even developing to the point of being unable to sleep and requiring termination of pregnancy. The palms and soles of the feet are common sites of itching, which persists until delivery, with most cases disappearing within 2 days after delivery, a few cases taking about a week to disappear, and it is rare for it to persist for more than 2 weeks.

　　In the days to weeks (average of 2 weeks) after the onset of itching, some patients may develop jaundice, with an incidence rate of 15% to 60% for intrahepatic cholestasis of pregnancy during pregnancy reported in the literature, with Wu Weixin reporting 55.4% and Dai Zhongying reporting 15%. The degree of jaundice is generally mild, sometimes only the cornea is slightly stained. The jaundice may persist for several days after delivery, and some may persist for more than a month after delivery; before and after the onset of jaundice, the patient's urine color becomes darker, and the stool color becomes lighter.

　　Intrahepatic cholestasis of pregnancy may also present with other symptoms such as vomiting, fatigue, and poor appetite.

　　Due to the main consequence of intrahepatic cholestasis of pregnancy being an increased incidence and mortality rate of perinatal morbidity, the aim of obstetric management should be to ensure a smooth full-term delivery of the fetus. It is necessary to understand the fetal movement of the pregnant woman, correctly collect blood and urine samples, understand the concentration of estriol, and master the changes in the placenta. It is also necessary to assist the pregnant woman in completing fetal monitoring, such as B-ultrasound and the five physical and biological indicators, in a timely manner to understand the condition of the fetus and placenta. At the same time, pay special attention to the changes in the concentration of bile acids in patients, and terminate the pregnancy promptly and rapidly in cooperation with the physician if there is an abnormal increase, in order to prevent intrauterine fetal death. If there is fetal distress and the fetus is mature, the pregnancy should be terminated immediately, and cesarean section is recommended, as vaginal delivery may increase the degree of fetal hypoxia. There are reports that active treatment of intrahepatic cholestasis of pregnancy during pregnancy can significantly reduce the perinatal mortality rate.

　　The examination of intrahepatic cholestasis of pregnancy mainly relies on clinical manifestations, medical history, or laboratory tests. For suspected cases of intrahepatic cholestasis of pregnancy, timely liver function and serum bile acid tests should be performed. The serum transaminase of pregnant women with this disease may be slightly or moderately elevated, with an increase of about 2-3 times the normal value. Increased serum bile acid is a sensitive indicator for the diagnosis of this disease, and its increase is often 10-100 times that of normal pregnant women, and the increase in serum bile acid is earlier than the occurrence of itching and jaundice, so many hospitals commonly perform routine serum bile acid testing at 28-30 weeks of pregnancy as a screening for intrahepatic cholestasis, in order to early detect the disease and take timely treatment measures.

　　For the laboratory diagnosis of intrahepatic cholestasis of pregnancy, the specific criteria can be followed as follows:

　　1. The clinical symptoms mainly表现为皮肤瘙痒 occur during pregnancy;

　　2. Abnormal liver function, mainly mild elevation of serum SGPT or SGOT, reaching about 60-100U, rarely exceeding 200U;

　　3. It may be accompanied by mild jaundice, with serum bilirubin approximately 1.1-5mg/dl;

　　4. Patients generally have good general condition, without obvious vomiting, anorexia, weakness, and other symptoms of other diseases;

　　5. Once delivery occurs, itching quickly subsides, liver function quickly returns to normal, and jaundice also disappears spontaneously;

　　Among the above symptoms and signs, itching is the most important, which may manifest as periumbilical itching, which gradually worsens, so it should be inquired about itching during each prenatal examination, and if present, SGPT should be re-examined to avoid missed diagnosis. Clinically, itching symptoms, the level of SGPT, and the presence or absence of jaundice are all associated with the perinatal prognosis, so it is recommended to divide intrahepatic cholestasis of pregnancy into mild and severe types based on clinical manifestations, in order to facilitate monitoring and treatment.

　　1. Mild type: slight itching, limited to the trunk, SGOT slightly elevated, but within 90U/dl, no jaundice.

　　2. Severe type: marked itching, affecting the whole body, may have scratch marks, SGPT > 90U/dl, jaundice may be visible, or bilirubin > 1mg/dl.

　　In differential diagnosis, it is mainly the combination of pregnancy and viral hepatitis. This disease often has symptoms of the digestive system, with significant elevation of SGPT and bilirubin, and the course of the disease does not improve or end rapidly with the termination of pregnancy, so it is not difficult to distinguish between the two diseases.

　　Pregnant women with intrahepatic cholestasis of pregnancy should strengthen rest, stay in a quiet and comfortable room, ensure sufficient bed rest. It is best to choose the left lateral position when resting to avoid the enlarged uterus from compressing the inferior vena cava; at the same time, pregnant women can also intermittent oxygen inhalation to improve the fetal hypoxia state; eat more fruits and vegetables appropriately, supplement vitamins and trace elements, avoid spicy and other irritating foods; pregnant women should wear cotton loose clothing and pants, keep the skin clean and dry; if the skin itches, do not scratch the itchy parts hard to avoid skin infection, and at the same time, you can choose other ways to relieve the skin itching symptoms and improve the liver function of pregnant women. For pregnant women with obvious itching, calamine can be applied externally; for those affected by sleep, you can take sedative-hypnotic drugs according to medical advice; for pregnant women with a smaller gestational age, dexamethasone intramuscular or intravenous injection should be given in time to promote fetal lung maturation and reduce estrogen production, to alleviate cholestasis. At the same time, pregnant women should also learn to count fetal movements, timely visit the hospital when the fetus is in distress, and terminate pregnancy in time to improve the perinatal prognosis.

　　In the field of traditional Chinese medicine, it is believed that intrahepatic cholestasis of pregnancy belongs to the category of 'itching of pregnancy body', and the etiology and pathogenesis are mainly due to Yin deficiency and blood dryness, internal dampness and heat. In terms of treatment, Yin deficiency and blood dryness are mainly nourished with blood, supplemented by kidney Yin nourishment, such as Danggui Dihuang Decoction (Zhenzhizheng) combined with Erzhi Pill (Yifang Jiji), the formula is as follows: Danggui 10g, Chuanxiong 10g, Baishao 15g, Shengdihuang 10g, Fangfeng 10g, Jingjie 10g, Huangqi 20g, Gancao 6g, Shouwu 15g; for internal dampness and heat, the main treatment is to clear heat and remove dampness, supplemented by spleen-nourishing and blood-nourishing, such as Danzhi Xiaoyao Powder (Xue Shi Yicai) combined with Sanwu Yinchen Decoction (Zhenzhizheng), the formula is as follows: Danshu 15g, Shanzhizi 6g, Chaihu 9g, Danggui 9g, Fuling 15g, Baizhu 15g, Baishao 15g, Bohe 6g, Zhigancao 3g, Wogeng 9g. Pay attention to treating diseases and ensuring pregnancy at the same time when taking the above Chinese herbs, which can achieve better therapeutic effects.