Cholestasis of pregnancy is a variant of gestational dermatosis caused by idiopathic intrahepatic stagnation of bile. It is manifested by itching of the skin, jaundice of the skin, dyspeptic symptoms, lightening of feces, darkening of urine. It is diagnosed on the basis of data on the level of bile acids, bilirubin, liver enzymes, hemostasis factors, supported by the results of liver ultrasound. Ursodeoxycholic acid, hepatoprotectors, choleretics, antihistamines, vitamin and mineral complexes, enterosorbents, detoxification therapy are used for treatment.
The prevalence of cholestasis in pregnant women (recurrent cholestatic hepatic jaundice, gestational pruritus) ranges from 0.1% to 2%. The disease is most often detected in Bolivia, Chile, Scandinavia, and China. Pathology is often of a family nature. The probability of developing gestational cholestasis increases in women who took estrogen before pregnancy-gestational oral contraceptives, antibiotics. The risk group also includes patients with intolerance to macrolides, erythromycins, gastrointestinal pathology, endocrine diseases. The risk of recurrence of obstetric jaundice during repeated pregnancy reaches 60-80%.
The etiology of gestational itching has not been definitively established to date. Since the disease is associated with pregnancy and often manifests itself in several women of the same family, hormonal shifts in predisposed patients most likely play a leading role in its development. Specialists in the field of obstetrics consider the main prerequisites for the occurrence of cholestasis during gestation:
- An increase in the concentration of estrogens. By the end of pregnancy, the level of estrogen hormones increases by more than 1000 times. By binding to hepatocyte receptors, estrogens enhance cholesterol synthesis, thereby changing the composition of bile. Under their influence, an imbalance of bile acids also occurs in pregnant women: the concentration of deoxycholic and henodeoxycholic acids decreases and the content of choleric acid increases. Due to a decrease in the activity of liver transport proteins, the level of bile acids in the bile decreases, respectively, their intake into the blood increases. The changes are more pronounced with high hyperestrogenism, characteristic of multiple pregnancies.
- Hypersensitivity to estrogens. A change in the colloidal balance of bile occurs in all pregnant women, but only some of them develop clinically pronounced cholestasis with itchy skin. Most likely, this is due to genetic abnormalities that change the sensitivity of liver cells, biliary tubules to estrogenic hormones or affect the activity of enzyme systems that ensure the synthesis and transport of bile acids. Confirmation of the hereditary nature of gestational cholestasis is a significantly more frequent detection of tissue antigens HLA-A31, HLA-w16, HLA-B8 in pregnant women with obstetric jaundice and their relatives.
An additional factor contributing to the disruption of bile outflow and an increase in the amount of bile acids in the blood plasma is the effect of progesterone. Progestins have a relaxing effect on smooth muscle fibers, which leads to deterioration of the motility of the gallbladder, bile ducts, which increases intrahepatic stagnation of bile. In addition, due to the slowing of intestinal peristalsis, the reverse absorption of bile acids is disrupted, their imbalance is aggravated.
The mechanism of occurrence of cholestasis in pregnant women is due to the irritating effect on the skin receptors of bile acids, the concentration of which in the blood increases with intrahepatic stagnation of bile. The leading pathophysiological link of hepatocellular cholestasis is a decrease in the fluidity of the basolateral and, somewhat less frequently, the canalicular membrane. The permeability of the cell membrane is impaired due to the insufficiency of hepatobiliary transport with the congenital failure of transporter proteins and an increase in cholesterol concentration due to the action of estrogens.
These factors reduce the activity of S-adenosylmethylsynthetase and inhibit the synthesis of S-ademethionine. As a result, the course of biochemical processes in hepatocytes is further destabilized, hepatocellular membranes lose phospholipids, the activity of Na-K-ATPase and other transport proteins decreases, the reserves of the main detoxifying substances (glutathione, taurine, other thiols and sulfates) decrease, which causes cell cytolysis with additional toxic components entering the blood. Cholemia and an increase in the level of bilirubin in the blood, the effect of metabolites on hepatocytes and biliary tubules, bile deficiency in the intestinal lumen form a typical clinical picture of the disease and its complications.
Specialists in the field of gastroenterology and hepatology, when systematizing the forms of intrahepatic gestational cholestasis, take into account the nature of changes in biochemical parameters and the severity of the disease. More favorable in prognostic terms is the partial bilirubin variant of the disorder with a violation of the synthesis and secretion of mainly bilirubin with the preservation of the metabolism of the remaining components of bile. In the partial choleacid form of cholestasis of pregnancy, which poses the greatest danger to women and children, the acceptance or secretion of bile acids is impaired during normal transport of other components. To choose the tactics of gestation support, it is important to take into account the severity of the disease:
- Mild. Skin itching is not clearly expressed. Transaminase activity is increased by 2-3 times, the content of alkaline phosphatase and gamma-glutamyltranspeptidase is increased. There are no other clinical and laboratory signs of the disorder. The risk of obstetric complications is minimal, gestation can be prolonged.
- The average degree. Pronounced itching of the skin. The activity of ALT, AST increased 3-6 times, increased concentrations of cholesterol, alkaline phosphatase, GGTP, impaired hemostasis. Ultrasound can determine the biliary sludge. The most common form of the disease with possible fetoplacental insufficiency and fetal development delay.
- Severe degree. In addition to skin itching and a significant increase in enzyme activity, there are laboratory signs of increasing coagulopathy, a clinic of gastroenterological disorders. Due to the high probability of a complicated course and even fetal death, it is recommended to terminate pregnancy prematurely.
Cholestasis of pregnancy symptoms
Usually the disease occurs at the 36-40 weeks of pregnancy, less often at the end of the 2nd trimester. At first, the disorder is manifested by skin symptoms. A pregnant woman experiences itching of varying intensity, from minor to excruciating. Itching is primarily localized in the palms, soles, then spreads to the back, abdomen, and other parts of the body, becoming generalized. Areas of excoriation (scratching) complicated by a secondary purulent process may be detected on the skin.
A non—permanent symptom of cholestasis is jaundice, which appears 1-2 weeks after the onset of itchy sensations, accompanied by darkening of urine and lightening of feces. In severe cases, there are complaints of nausea, belching, heartburn, loss of appetite, heaviness in the epigastrium, dull pains in the right hypochondrium, rarely vomiting. The pregnant woman becomes sluggish, apathetic, inhibited. The disease passes on its own 7-15 days after delivery.
Cholestasis of pregnancy usually does not serve as a contraindication for the continuation of gestation, however, with moderate and severe course, it has an adverse effect on it. With prolonged cholemia, energy metabolism is sharply disrupted, hypoxia increases, a cytotoxic effect occurs, which lead to fetoplacental insufficiency, fetal development delay, and an increase in perinatal mortality up to 4.7%. With recurrent cholestasis, antenatal fetal death is noted 4 times more often than in normal pregnancy. Up to 35% of deliveries end with the birth of a premature baby with signs of hypoxia.
With cholestatic hepatic jaundice of pregnant women, premature birth is observed in 12-44% of cases, respiratory distress syndrome is more often diagnosed, meconium in amniotic fluid is determined. Due to insufficient absorption of vitamin K, hemostasis disorders develop. As a result, the risk of obstetric coagulopathic bleeding, DIC syndrome increases.
Increased likelihood of postpartum endometritis. Gestational itching tends to recur during subsequent pregnancies, while taking combined oral contraceptives. In the long-term period, such patients often suffer from cholelithiasis, cholecystitis, non-alcoholic forms of hepatitis, cirrhosis of the liver, chronic pancreatitis.
Since itching and yellowing of the skin are detected not only with cholestasis of pregnancy, but also with a number of skin, infectious, somatic diseases, the task of diagnostic search is to exclude signs characteristic of other disorders that could arise or worsen during gestation. The recommended examination plan for patients with suspected cholestasis of pregnancy includes the following laboratory and instrumental methods:
- Determination of the level of bile acids. The study is considered screening and allows detecting cholestasis at the preclinical stage in predisposed pregnant women. Against the background of a general increase in the concentration of serum bile acids, the content of cholic acid was increased and the level of henodeoxycholic acid was reduced.
- Liver tests. Markers of intrahepatic cholestasis are a moderate increase in the content of direct bilirubin, α- and β-globulins, triglycerides, β-lipoproteins. Cholesterol is clearly elevated. The albumin level is slightly reduced. There is an increase in the activity of alkaline phosphatase, GGGT, AlT, AsT, 5’-nucleotidase.
- Hemostasiogram. The moderate and severe course of the disease is characterized by changes in the hemostasis system with an increase in APTT and prothrombin time.
- Ultrasound of the liver and biliary tract. The liver of a pregnant woman has a normal size, homogeneous echostructure. It is possible to change the acoustic density of the liver tissue, the appearance of biliary sludge. The gallbladder is often enlarged, the intrahepatic bile ducts are dilated, the echogenicity of their walls is increased.
Gestational cholestasis is differentiated from other dermatoses of pregnant women, acute fatty hepatosis during gestation, HELLP syndrome, late gestosis, viral hepatitis, cholelithiasis, drug-induced cholestatic jaundice, liver cancer, hereditary hepatic pathology (hemochromatosis, Konovalov-Wilson disease, Bailer syndrome) and other diseases. Infectious mononucleosis and cytomegalovirus infection are excluded. According to the indications, the patient is consulted by a dermatologist, an infectious disease specialist, a gastroenterologist, a hepatologist, a toxicologist, an oncologist.
When accompanying women with gestational jaundice, a wait-and-see tactic with careful monitoring of laboratory parameters and fetal condition is preferable. The main therapeutic task is to eliminate the symptoms of bile stagnation, which negatively affect the child’s body. The scheme of drug treatment depends on the severity of gestational cholestasis and usually involves the appointment of such drugs as:
- Ursodeoxycholic acid. The drug affects the key links of pathogenesis and is the main one in the treatment of the disorder. Due to its high hydrophilicity, it effectively protects the bile ducts from the action of hydrophobic bile acids, stimulates the withdrawal of hepatotoxic components of bile. It is safe for the fetus.
- Hepatoprotectors and choleretics. Drugs that affect the state of liver cells and bile secretion can reduce the risk of damage to hepatocytes, improve their functioning, and reduce congestion in the biliary system.
With generalized itching, a rapid increase in laboratory parameters, especially the detection of high cholemia, enterosorbents, detoxification therapy (hemosorption, plasmapheresis) are used to remove substances from the body that cause itchy sensations. In all forms of the disease, the use of antioxidants (ascorbic acid, vitamin E) is effective. It is possible to prescribe antihistamines that soften itching. The use of systemic glucocorticosteroids is limited due to possible toxic effects on the fetus.
Drug therapy of cholestasis is combined with diet correction. It is recommended to supplement the diet of a pregnant woman with protein products (chicken, beef, veal), dietary fiber, fat-soluble vitamins, folic and linoleic acids, limit the use of fatty, spicy, fried.
With mild and moderate severity of the disease, pregnancy ends with natural childbirth in a physiological period. If cholestasis proceeds with intense jaundice, cholemia approaches 40 mmol / l, there is a threat to the life of the fetus, early delivery is carried out at a period of 36 weeks. Caesarean section is performed with threatening or incipient fetal asphyxia, detection of other obstetric indications.
Prognosis and prevention
A favorable outcome of gestation is most likely with mild and moderate cholestasis of pregnancy. In severe cases, the prognosis worsens, especially in the case of manifestation of the disorder in the second trimester. For preventive purposes, patients who suffered cholestatic jaundice during a previous pregnancy, have a hereditary burden for this disease or are carrying several fetuses, early registration in a women’s clinic, regular examinations by an obstetrician-gynecologist, scheduled consultation by a gastroenterologist, screening blood tests for bile acids are recommended.