Intrahepatic cholestasis of pregnancy
Introduction
Introduction to intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy (ICP) is a unique complication of middle and late pregnancy. It is characterized by clinical itching and elevated bile acid, which mainly harms the fetus and increases the morbidity and mortality of perinatal children. The greatest risk of pregnancy to the disease is the unpredictable sudden death of the fetus, which is related to the extent of the condition. The disease is recurrent, and it can quickly disappear after delivery. It often recurs when it is re-pregnancy or oral estrogen contraceptives. The incidence of ICP is 0.8% to 12.0%, with obvious geographical and ethnic differences, and the incidence rates in Shanghai and Sichuan are high. basic knowledge Sickness ratio: 0.0001% Susceptible population: pregnant women Mode of infection: non-infectious Complications: premature birth, fetal distress, postpartum hemorrhage
Cause
Causes of intrahepatic cholestasis of pregnancy
Abnormal estrogen metabolism (45%)
Estrogen levels in pregnant women increase significantly, estrogen can reduce Na+-K+-ATPase activity, reduce energy supply, leading to bile acid metabolism disorders; estrogen can increase the ratio of cholesterol and phospholipids in liver cell membrane, and reduce fluidity, affecting The permeability of bile acid blocks the bile outflow; estrogen acts on the estrogen receptor on the surface of hepatocytes, altering the protein synthesis of hepatocytes, resulting in increased bile reflux. The combination of the above factors may lead to the occurrence of ICP. Clinical studies suggest that estrogen is not the only cause of ICP disease, may be caused by abnormal estrogen metabolism and high sensitivity of the liver to physiologically increased estrogen during pregnancy.
Genetic factors (20%)
Epidemiological studies have found a family history of intrahepatic cholestasis of pregnancy, and the incidence of ICP is significantly higher in women with a history of ICP in their mothers or sisters, suggesting that genetic factors play a role in the development of ICP.
Drugs (10%)
Some drugs that reduce bile duct transport of bile, such as azathioprine taken after kidney transplantation, can cause ICP.
Environmental factors (10%)
The incidence of ICP is related to the season, and the incidence rate in winter is higher than that in summer.
Pathogenesis
1. The relationship between estrogen and ICP
(1) Clinical basis: There are many clinical manifestations suggesting that estrogen levels are too high may be the cause of ICP induction. The following are listed as follows: 1 ICP occurs in the third trimester of pregnancy, at the peak of estrogen secretion; 2ICP in twins The incidence rate is significantly higher than that of singleton. Shanghai Sixth People's Hospital reported that the incidence of ICP in twins is 6 times higher than that of singletons. The volume of placenta may be significantly larger than that of singletons. The secreted estrogen is more than singleton. 3 The incidence of cholestasis in women with estrogen and progestin-containing contraceptives is very similar to that of ICP; 4 women who use contraceptives develop ICP during pregnancy, and the recurrence rate is higher when they are pregnant again.
(2) Laboratory research: Many scholars use animals to study the effects of estrogen on bile secretion. The estrogen may cause cholestasis through the following pathways: 1 increased permeability of bile; 2 sodium, potassium-triphosphate in the sinusoidal space Decreased activity of enzyme (Na-K-ATPase) hinders bile salt transport; 3 cell membrane fluidity decreases in sinusoidal region, causing obstruction of bile salt passage; 4 estrogen metabolite: D-loop glucuronide estrogen and The structure of cholic acid is similar and becomes a competitive inhibitor of cholic acid carriers. The production of large amounts of estrogen during pregnancy leads to cholestasis in some women during pregnancy; 5 estrogen receptors in the liver and protein synthesis: it is speculated that estrogen can make organic The synthesis of anion and bile acid carriers is reduced, and it also affects the translocation of organic anions of binding proteins in cells, and the operation of secreting vesicles to the area of the bile duct.
2. The relationship between ICP and progesterone
Progesterone is also a hormone secreted by the placenta. Although humans usually have good tolerance to progesterone, recent clinical observations and experiments have found that progesterone is also associated with the onset of ICP. Bacq et al (1998) studied 13 patients with ICP. Among them, 10 cases have been treated with progesterone (0.2-1.0g/d) before ICP, and some patients naturally return to normal after stopping the treatment. However, little is known about the mechanism of progesterone-induced intrahepatic cholestasis. Early studies suggested that the mechanism of cholestasis caused by progesterone during pregnancy was similar to that of estrogen. Meug et al. (1997) simultaneously measured the blood and urine bile acid and progesterone metabolites in ICP patients and normal pregnant women. The result was 5-pregnancy in ICP pregnant women. The vulcanized product of alkane-3,20-progesterdiol increases, while the glucuronide-bound progesterone product does not change or even decrease. The progesterone metabolite in blood is mainly excluded from bile, and about 30% of progesterone sulfate The method is combined with pyrosulfate and may be transported by organic anion carrier. The increase of progesterone pyrosulfate in the blood of ICP patients may reflect the impairment of bile duct secretion, but glucuronic acid does not change. In ICP patients, sulphate secretion of sulfated quinone compounds is selective, Ding Xilai et al (2001) used pregnant mice for animal experiments, with progesterone at a daily dose of 150mg / kg from the 13th day of pregnancy to the 20th day of pregnancy intramuscular injection, Results In addition to elevated serum liver enzymes, bile acids and bilirubin, the telangiectasia in the ultrastructure visible under an electron microscope, with high electron density deposits inside, resulted in estrogen blood in pregnant mice. Biochemical performance, liver pathological changes are similar, observed from electron microscopy, the change is more similar to human ICP, therefore, progesterone may also be the cause of ICP, but its true mechanism of action has yet to be further studied at the molecular biology level. .
3. The relationship between ICP and anticardiolipin antibodies
Anticardiolipin antibody (ACA) is an autoimmune antibody and an important manifestation of autoimmune abnormalities. The target antigen of ACA is cardiolipin located on vascular endothelial cells and platelet membrane. ACA acts on the target and will Injury of vascular endothelial cells reduces the synthesis of prostaglandin I2 (PGI2); at the same time activates platelets, causes platelets to adhere, aggregates and releases thromboxane A2 (TXA2), while villus vasculopathy and extensive thrombosis and infarction in the placental vessels are The main pathological basis of poor pregnancy outcome in patients with ACA-positive, circulatory ACA levels in ICP patients significantly increased, suggesting that there may be some relationship between the two, from decreased blood rheology, abnormal lipid metabolism and increased serum laminin (with the base Observation of membrane damage), ICP and pregnancy-induced hypertension have some of the same changes, so some scholars believe that immune dysfunction and autoimmune disorders may also be common to both diseases, one of the pathophysiological changes associated with the disease, and liver cells may Also affected by ACA, resulting in hepatic blood flow slow, liver cell dysfunction, intrahepatic cholestasis, these still have For further study.
4. The relationship between selenium and ICP
Selenium (Se) is a trace element. In order to meet the needs of pregnant women during pregnancy, the intake of Se increases. Se is an active component of glutathione peroxidase, and its function is related to vitamin E. From epidemiological observations, the incidence of ICP seems to have seasonal changes. Reyes et al. (2000) measured the concentration of selenium in blood. Compared with 9 years ago, Se increased in non-pregnant women from (0.85±0.13) mol. /L rose to (1.43±0.34) mol/L, which decreased to (1.08±0.25) mol/L in late pregnancy. To study its seasonal relationship, Reyes et al. tried to separate blood from Se, Zn and Cu in different seasons of pregnant women. As a result of the horizontal change, the blood level of Se is as high as (1.34±0.19) mol/L in summer, while Zn and Cu are decreased. Reyes et al believe that the decrease in the incidence of ICP may be related to the increase of Se in recent years. The decrease in the incidence rate in summer is related to the blood level of selenium in summer. In China, Wang Zhuchen et al. (2000) also studied the selenium in the blood of ICP patients, the level of selenium in the placenta and its relationship with glutathione peroxidase. ICP patients, regardless of the selenium in the blood and the selenium in the placenta are lower than normal, and the valley The activity of glycopeptide peroxidase also decreased, showing consistency; in normal pregnancy, anti-oxidation can prevent oxidative damage of estrogen, while in ICP patients, when glutathione peroxidase is decreased, the antioxidant defense ability of cells decreases. The increase in estrogen load leads to the formation of free radicals, affecting the cell membrane of the liver and reducing the ability to excrete bile.
Prevention
Prevention of intrahepatic cholestasis during pregnancy
Because the main consequence of ICP is the increase in perinatal morbidity and mortality, the purpose of obstetric treatment should be to make the fetus smoothly deliver in full term. If there is fetal distress and the fetus is mature, the pregnancy should be terminated and the cesarean section Production is appropriate, because vaginal delivery will increase the degree of fetal hypoxia, it has been reported that ICP has been actively treated, can significantly reduce perinatal mortality.
Complication
Complications of intrahepatic cholestasis during pregnancy Complications, premature delivery, fetal distress, postpartum hemorrhage
Premature birth
In 1966, Haemmerli reported 18 cases of ICP patients, a total of 43 pregnancies, 23 times ending with preterm birth, of which 22 preterm births were concentrated in 8 patients. In 1976, Reid reported 56 cases of ICP, 50 cases of live births and 18 cases of premature delivery, premature rate. 36%, 13 cases of body weight <2500g, 11% of perinatal mortality, 24 cases (18%) of 134 cases of premature birth in China, and 6% of perinatal mortality. In 1984, Laatikainen reported 117 cases of ICP during pregnancy. 35 5 weeks, 1987, Dai Zhongying and other reports 250 cases of ICP average pregnancy was 38.7 weeks, 34 cases (13.6%) of premature birth, neonatal weight 2500g 21 cases (8.2%); the above figures indicate that the incidence of ICP premature birth is indeed obvious Increase. For the cause of premature birth, Laatikainen believes that the fetus of ICP pregnant women is incapable of converting the 16-hydroxylate-dehydroepiandrosterone (DHAS) produced by the placenta into a relatively inert estriol, so a large number DHAS is converted to active estradiol through other pathways of the placenta leading to premature labor. Recently, animal experiments have shown that bile acid can increase the contractility of uterine muscle in mice. Bile acid can also promote the release of prostaglandins, which induces uterine contraction. Premature birth.
2. Fetal distress
Among the 56 cases reported by Reid (1976), 6 stillbirths, the perinatal mortality rate was 11%, 5 of the 50 live births were not called cesarean section because of the head basin, and the remaining 45 cases were severely contaminated by amniotic fluid. In the case of (27%), 8 cases of fetal heart rate <100 beats/min, the incidence of stillbirth and fetal distress in pregnancy pruritus complicated with jaundice was much higher than that in simple pruritus. Wu Weixin reported 134 cases of perinatal death in ICP. For example, in 5 cases of stillbirths occurred suddenly before labor, Dai Zhongying (1986) reported 32 cases of perinatal deaths in 1984, the perinatal mortality rate was 15.6 , and in the same year 74 cases of ICP were 5 perinatal children. Death (67.6 ), 4 of which are stillbirths or stillbirths, will die in labor or labor. According to the above data, the incidence of fetal distress in ICP is higher than normal.
Laatikainen (1977) divided 86 cases of ICP into three groups according to the increase of serum bile acid level, and found that the higher the bile acid level, the higher the incidence of fetal distress.
In 1984, Laatikainen reported 117 cases of ICP, which again proved that the higher the serum bile acid level, the higher the fetal distress rate. Therefore, the dynamic determination of serum bile acid level can be used as a method to observe the fetal prognosis of ICP patients.
The cause of fetal distress is still unclear. Laatikainen (1977) studied the relationship between fetal bile acid levels and fetal distress in ICP pregnant women. In 41 cases (1 twin) ICP, there were 16 cases of fetal distress, ICP fetal cord blood CA The level was 3.74g/ml, while the umbilical cord blood CA level in the normal control group was only 0.94g/ml; in the 22 cases of ICP fetal cord blood CA level higher than 3.74g/ml, there were 12 cases of fetal distress, less than 3.74g/ Only 4 of the 20 cases of ml have fetal distress. Animal experiments have also shown that oral or intravenous injection of cholic acid can cause liver cell damage; therefore, Laatikaine believes that ICP occurs in the mother, which increases the CA in the fetus and has adverse effects on the fetus. Changes in the metabolism of fetal steroids can also cause distress in the fetus. In 1991, Sepulveda reported that there was a relationship between the effects of different concentrations of CA on free villus veins, that is, there was a significant relationship between vasoconstriction at high concentrations, so severe ICP Hyper-CA can cause vasospasm, increased resistance, decreased blood flow, and decreased oxygen exchange capacity, resulting in intrauterine distress.
In recent years, it has been suggested that fetal distress in ICP patients has a certain relationship with the reduction of intercavity. In 1980, Costoya et al. observed by light microscopy and electron microscopy that the number of syncytocytes in the placenta of ICP patients increased, the villus matrix was sparsely hydrophobic, and the trophoblasts increased. Thick, the number of cytotrophoblast cells is significantly increased, Costoya believes that these changes are primary or secondary, because the result of these lesions is the reduction of the villus gap, the maternal blood flow in the villus cavity is reduced per unit time, resulting in the fetus In 1987, Liu Boning et al. performed tissue measurement on 20 ICP placenta to determine a number of parameters, and compared 20 placental mothers with normal gestational age, and found that the interstitial space of the ICP group was significantly smaller than that of the normal control group. <0.001, while the other parameters have a P value of >0.1. Therefore, it can be considered that the narrow interstitial space may also be an important cause of the increase in ICP perinatal mortality.
3. Postpartum hemorrhage
Reid (1976) reported 50 cases of ICP vaginal delivery, 10 cases of bleeding > 500ml, including 5 cases of > 2000ml; and Frielaender also had the same report; in 1988 Hou Lirong et al observed 158 cases of postpartum ICP bleeding, and 158 For normal maternal controls with the same obstetric conditions, the average bleeding volume at 24 hours after birth was 234 ml and 177.1 ml, respectively. The difference was significant. Reid believed that the placental secretion of ICP in pregnant women was insufficient, the absorption of vitamin K was reduced, and the liver was synthesized. The amount of factor II, VII, IX, and X is also reduced to cause postpartum hemorrhage.
4. Obstetric complications
(1) ICP combined with hypertensive disorder complicating pregnancy: In 1987, when Dai Zhongying summed up 250 cases of ICP, he found that the number of patients with hypertensive disorder complicating pregnancy was as high as 24%, and then Huang Yazhen concluded that there were 451 cases of ICP in 10243 births from 1986 to 1994. 4.4%), 901 cases of pregnancy-induced hypertension (8.8%), 79 cases of ICP and hypertensive disorder complicating pregnancy (0.77%), the incidence of hypertensive disorder complicating pregnancy in the ICP group was 17.52%, and pregnancy The incidence of ICP in the hypertensive disease group was 8.72%, which was significantly higher than that in the general population with ICP and hypertensive disorder complicating pregnancy. ICP pregnancy-induced hypertension and ICP with hypertensive disorder complicating pregnancy 3 The perinatal mortality rate of the group was 18.81%, 13.30% and 59.52%, respectively. The latter was significantly higher than the former two. Therefore, for ICP patients with concurrent hypertensive disorder, they should be treated more actively, including strengthening the fetus. Monitoring, promoting fetal lung maturation and timely termination of pregnancy.
(2) ICP combined with multiple pregnancy: In 1987, when Dai Zhongying summarized 250 cases of ICP, he noticed that there were 5 cases of twins. In 1989, Gouzale reported that 62 cases of twins with ICP were up to 20.9%, and ICP with single tire. The incidence was 4.7%, the difference was extremely significant. In the quantitative determination of urinary estriol (E3) in the two groups, the twins were significantly higher than the singletons. Although the degree of statistical difference has not been reached, it can be explained that estrogen is formed in ICP. The role of the role, in 1997, Tao Minfang and other reports in 12,886 births, a total of 90 cases of twins (7 ), analysis of 80 cases of complete twins, including 24 cases (30%), with 12,796 ICP 540 cases (4.2%) with ICP in a single fetus were compared with each other. There was a significant difference between the two. The twins were combined with ICP and not with ICP. The gestational age was 34 3 weeks and 36 1 week, respectively. The incidence of hypertensive patients was 54.2% and 33.9%, respectively, and the post-production bleeding was 37.5% and 16.1%, respectively, and the difference was significant.
Symptom
Symptoms of intrahepatic cholestasis of pregnancy Common symptoms Nausea, loss of appetite, anorexia, fatigue, skin, itching, liver function, jaundice, bile retention
ICP is mainly characterized by skin itching in the middle and late pregnancy without skin damage. A few cases occur before the 25th week of pregnancy. Itching is often the main complaint. Usually itching begins in the palm of the hand, the sole of the foot and the distal part of the limb, and then expands to the proximal end. Severe cases can affect the face, neck and ears, but generally cause itching on the surface of the mucous membrane. This kind of itching can not be relieved by scratching. It is difficult to treat clinically. Itching can be continuous or intermittent. For systemicity, it can also be limited. The degree can be light or heavy. The lighter does not affect daily work. Medium and severe itching can affect the patient's sleep. Most patients have itching at night, and some patients show extreme fatigue due to severe itching. Or irritability, the cause of pruritus in ICP patients is unknown.
Examine
Examination of intrahepatic cholestasis of pregnancy
1. SGPT and SGOT Most patients with ICP had a slight increase in SGPT and SGOT. Among 134 patients with Wuweixin, 111 patients had SGPT, and 81 patients had abnormal values, with a mean value of 121 U. All of the 250 patients reported by Dai Zhongying were SGPT. The increase was 216 cases (86.4%), the mean value was 101.6U, of which more than 200U were less; Riszkowiski reported 43 cases of simple ICP 29 cases, the average SGPT and SGOT were 141U and 69U, according to most scholars, SGPT More sensitive than SGOT.
Bilirubin
In the early literature, ICP patients detected more elevated serum bilirubin levels, such as Haemmerli (1966) reported 29 cases of ICP, serum bilirubin levels were elevated, but in recent studies bilirubin levels rose There are not many such highs. For example, Wu Weixin reported that 101 cases of total bilirubin level were measured, and 66 cases of elevation were found. The mean value was 37.45mol/L (2.19mg/dl) [18.47218.88mol/L (1.0812.8) Mg/dl)], 89 cases of bilirubin were measured in 1min, 59 cases were elevated, the mean value was 16.93mol/L (0.99mg/dl), and 176 cases of ICP reported by Dai Zhongying, serum total bilirubin increased 36 In the case (20.5%), the mean value was 18.90 mol/L (1.69 mg/dl), the highest was 85.5 mol/L (5.0 mg/dl), and the increase in bilirubin in 1 min was 28 (15.9%), with a mean of 11.80. mol/L (0.69 mg/dl).
3. Bile acid
Bile acid is a general term for bile acids in bile. There are two main types of human bile acids: bile acid (CA) and chenodeoxycholic acid (CDCA). In the colon, bacteria can convert cholic acid into deoxycholic acid (DCA). It can convert goose deoxycholic acid into lithocholic acid. Both DCA and lithocholic acid are secondary bile acids. When liver cells are damaged or liver function is reduced, bile acid excretion is not good, and it accumulates in surrounding serum.
CA and CDCA in patients with ICP generally increase gradually after 30 to 32 weeks of gestation, and increase by 20-fold and 10-fold at 40 weeks of gestation. The mean CA is 9.64 mol/L, the CDCA is 4.74 mol/L, and the DCA is 1.07. mol / L, CA: CDCA = 2: 1, pregnancy simple itching without liver damage, CA value is only slightly elevated, a small number of patients can be higher than the upper limit of normal.
Ultrasound examination: The gallbladder of this patient increased by about 60% compared with normal pregnant women.
Diagnosis
Diagnosis and identification of intrahepatic cholestasis of pregnancy
diagnosis
For the diagnosis of ICP, the following criteria can be specified:
1. The main symptoms of pruritus in pregnancy occur.
2. Abnormal liver function, mainly a slight increase in serum SGPT or SGOT, reaching 60-100U, less than 200U.
3. May be associated with mild jaundice, serum bilirubin at 18.81 ~ 85.50 / mol / L (1.1 ~ 5mg / dl).
4. The patient is generally in good condition with no obvious vomiting, loss of appetite, weakness and other symptoms of the disease.
5. Once childbirth, itching quickly subsided, liver function quickly returned to normal, and jaundice also resolved on its own.
In the above symptoms and signs, itching is the most important and can be mild, so it should not be missed every time before antenatal examination.
Differential diagnosis
Mainly pregnant with viral hepatitis, the disease often has digestive symptoms, SGPT and bilirubin increased significantly, the course of the disease does not quickly improve or end with the termination of pregnancy, so it is not difficult to distinguish the two diseases.
