RU2537120C2 - Method of treating and managing pregnant women with drug-induced hepatitis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to obstetrics and gynaecology, and can be used for treating and managing the pregnant women suffering drug-induced hepatitis. Establishing a diagnosis of drug-induced hepatitis requires oral administration of the herbal hepatoprotectors Carsil, or Hepabene, or the vitamin-free essential phospholipids Eslidin per os or Essentiale forte N intravenously, per os in standard doses with a cessation of any other drug-induced therapy, in the 1^st trimester of pregnancy in case of observing a symptom-free increase of transaminase activity within 3 normal values and no counter-indications. In the 2^nd trimester, a serum transaminase level up to 5 normal values requires prescribing ademetionine 400 mg intravenously N 7-10, then per os 1,600 mg/day. The therapeutic course makes 1 month. Ademetionine 800 mg intravenously N 10 + ursodeoxycholic acid 12 mg/kg/day are prescribed if observing the daily serum transaminase level of 5 to 10 normal values. Prescribing ademetionine 800 mg/day intravenously + ursodeoxycholic acid 12 mg/kg/day + prednisolone 90 mg/day is used for the daily serum transaminase level of more than 10 normal values. In the 3^rd trimester, the daily serum transaminase level of below 5 normal values requires administering ademetionine 800 mg/day intravenously N10 + ursodeoxycholic acid 13 mg/kg/day. The transaminase level of 5 to 10 normal values requires prescribing ademetionine 800 mg/day intravenously + ursodeoxycholic acid 13 mg/kg/day + prednisolone 90 mg/day intravenously. A progressive increase of the daily transaminase level of above 10 normal values with underlying therapy with ademetionine 800 mg/day intravenously, ursodeoxycholic acid 13 mg/kg/day, prednisolone 120 mg/day intravenously with 3 days expected, a decrease of the daily transaminase level or a stabilization thereof are accompanied by continuing the therapy with the progression follow-up, including hepatic cytolysis values - an increase of the hepatic cytolysis values; an increase thereof is accompanied by prescribing the adequate therapy. The postpartum therapy is continued completely until liver function tests are normalised.

EFFECT: method enables preventing the pregnancy complications ensured by the timely diagnosis of drug-induced hepatitis in the pregnant women, the adequate drug-induced therapy differentiated by gestational age and a degree of manifestation of hepatic cytolysis and aiming at reducing a hepatic pathological process.

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Description

The invention relates to medicine, namely to obstetrics and gastroenterology, and can be used to treat pregnant women with drug hepatitis.

The problem is caused, firstly, by the significantly increased incidence of drug-related hepatitis in pregnant women in Russia as a whole, which poses a serious threat to the health of pregnant women, the course of pregnancy and the fetus, and secondly, the lack of a suitable treatment methodology and tactics for pregnant women depending on gestational age and activity of the pathological process in the liver.

The results of the study indicate that the most common drug-related hepatitis in pregnant women is associated with those taken before pregnancy, including in connection with IVF, or during pregnancy, hormonal estrogen and progesterone-containing drugs, multivitamin-mineral complexes, iron and calcium preparations, antibacterial drugs, non-steroidal anti-inflammatory drugs, etc.

All this leads to the fact that:

1. The most severe course of drug hepatitis is noted in the 3rd trimester of pregnancy. It is accompanied by a high risk of complications of pregnancy - gestosis, acute fatty liver of pregnant women, coagulopathy, fetoplacental insufficiency, and often - early delivery.

2. The development of severe drug hepatitis in the 2nd trimester of pregnancy in the absence of adequate treatment is an indication for premature termination of pregnancy for medical reasons.

3. In the 1st trimester, the prognosis is less serious. Under the condition of dynamic observation and “response to treatment” (waiting period of up to 14 days with transaminases <10 norms), prolongation of pregnancy is acceptable.

4. The cholestatic variant of drug hepatitis is easier than cytolytic, but resolves more slowly and more often causes coagulopathy.

5. A poor prognosis is associated with the severity of cytolysis, hyperbilirubinemia and jaundice (mortality in acute liver failure reaches 50%).

Studies have established that treatment of pregnant women with drug hepatitis should be determined:

1) the prevailing mechanism (direct hepatotoxic (cytolytic, cholestatic or mixed) effects of drugs, toxic effects of their metabolites, idiosyncrasy (individual intolerance) or immunoallergic liver damage);

2) hepatitis activity (degree of cytolysis),

3) the presence of cholestasis,

4) gestational age,

5) the condition of the fetus.

A number of features of the course of drug hepatitis in pregnant women have been identified that determine the tactics of managing patients:

- Malosymptom (weakness, skin itching) or asymptomatic clinic with a manifestation at the stage of severe violations of the liver.

- The prevalence of cytolytic or mixed syndrome with a tendency to progression (especially in the III trimester and after childbirth).

- Complex differential diagnosis due to frequent comorbidity, the need to perform many studies in a short time with limited diagnostic capabilities.

- The need for dynamic, and with high activity, daily multicomponent monitoring of liver function and hemostasis, as well as more frequent monitoring of the fetus.

- The complexity of the treatment, providing, on the one hand, the appointment of adequate medicines, and on the other, the need to ensure the safety of treatment for the pregnant woman, the course of pregnancy and the fetus.

- High probability of fatal complications for women and fetuses (acute fatty liver of pregnant women, HELLP syndrome, Budd-Chiari syndrome and coagulopathy (↑ PTV and APTT due to progression of cytolysis and vitamin K deficiency), especially in the third trimester.

- The need for timely decision-making on early delivery or artificial termination of pregnancy + high responsibility associated with the adoption of this decision.

- The need to determine the type of delivery and the method of anesthetic administration, taking into account the hepatotoxicity of most anesthetics and the high likelihood of bleeding and DIC (the advantage is caesarean section and epidural anesthesia).

- Preservation (progression) of symptoms of cytolysis after childbirth, requiring prolonged therapy (including glucocorticosteroids) and the need to decide on the possibility of breastfeeding.

There is a method of treating hepatosis [Obstetrics: national leadership / Ed. E.K. Aylamazyan, V.A. Kulakova et al. M .: GEOTAR-Media. 2007. 997-998 pp.] (A wide and insufficiently differentiated group of liver diseases) in pregnant women.

The known method involves the use of ademetionine, ursodeoxycholic acid and some other hepatoprotectors, but without specifying the method of their use, dosages, without taking into account the activity of hepatic cytolysis and the characteristics of the appointment of drug therapy at different stages of pregnancy.

The technical result consists in preventing pregnancy complications due to timely diagnosis of drug-induced hepatitis in pregnant women, conducting adequate, differentiated by the gestational age and severity of hepatic cytolysis drug therapy aimed at stopping the pathological process in the liver.

The essence of the invention lies in the fact that in the method of treatment and tactics of managing pregnant women with drug hepatitis after establishing a diagnosis of drug hepatitis in the 1st trimester with an asymptomatic increase in transaminase activity within 3 norms and the absence of contraindications, eslidine is taken orally 2 capsules 3 times a day when canceled other drug therapy. Treatment is carried out within 1 month. In the 2nd trimester, at a serum transaminase level of up to 5 norms, take ademethionine 400 mg IV 7-10, then orally 1600 mg / day, the treatment course is 1 month, at a serum transaminase level from 5 to 10 norms, ademetionin 800 mg a / in N 10 + ursodeoxycholic acid 12 mg / kg / day, with a serum transaminase level of more than 10 norms - ademethionine 800 mg / day iv / ursodeoxycholic acid 12 mg / kg / day + prednisolone iv 90 mg / day. In the 3rd trimester, at a serum transaminase level of up to 5 norms, ademethionine 800 mg / day i / v N10 + ursodeoxycholic acid 13 mg / kg / day is taken, at a transaminase level from 5 to 10 norms, ademethionine 800 mg / day iv ursodeoxycholic acid 13 mg / kg / day + iv prednisolone 90 mg / day, with an increase in serum transaminases above 10 norms take ademethionine 800 mg / day iv + ursodeoxycholic acid 15 mg / kg / day + iv prednisolone 120 mg / day In the absence of a decrease in hepatic cytolysis within 3 days, early delivery is performed. In the postpartum period, ademetionine 1600 mg / day + ursodeoxycholic acid 12 mg / kg / day is taken orally. Therapy is continued until the normalization of “liver tests” +2 weeks. In all trimesters of pregnancy, therapy is continued under the condition of monitoring the dynamics - a decrease in the activity of indicators of hepatic cytolysis or adequate therapy is prescribed when they increase.

The method is as follows.

In the 1st trimester, with an asymptomatic increase in the activity of transaminases within 3 norms and the absence of contraindications, eslidine is taken orally 2 capsules 3 times a day when another drug therapy is canceled. Treatment is carried out for 1 month, on an outpatient basis with weekly biochemical monitoring of serum transaminases, bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, prothrombin, APTT, MHO, protein fractions. With a higher activity of cytolysis and no response to treatment within 2 weeks - hospitalization with the decision on the use of glucocorticosteroids and termination of pregnancy.

In the 2nd trimester:

- at a level of serum transaminases up to 5 norms - use ademetionine (heptral) 400 mg iv 7-10, then orally 1600 mg / day. The course of treatment is 1 month.

- at a level of serum transaminases from 5 to 10 norms, ademetionine 800 mg iv 10% ursodeoxycholic acid 12 mg / kg / day.

- at a serum transaminase level of more than 10 norms, ademetionine 800 mg / day iv + ursodeoxycholic acid (ursosan) 12 mg / kg / day + prednisolone iv 90 mg / day.

- in the absence of positive dynamics (waiting period of 5-7 days), an abortion is performed for medical reasons.

In the 3rd trimester:

- at a level of serum transaminases up to 5 norms, ademetionine 800 mg / day iv N10 + ursodeoxycholic acid (ursosan) 13 mg / kg / day.

- at a level of transaminases from 5 to 10 norms, ademetionine 800 mg / day iv + ursodeoxycholic acid (ursosan) 13 mg / kg / day + prednisolone iv 90 mg / day.

- with an increase in the level of serum transaminases over 10 norms, ademetionine 800 mg / day iv + ursodeoxycholic acid 15 mg / kg / day + iv prednisolone 120 mg / day are taken. In the absence of a decrease in hepatic cytolysis within 3 days, early delivery is performed due to the high risk of complications.

In the postpartum period, ademetionine 1600 mg / day + ursodeoxycholic acid 12 mg / kg / day is taken orally.

Short-term progression of cytolysis is observed (usually within 5-7 days), therefore, therapy continues in full until the normalization of “liver samples” +2 weeks, under the supervision of a therapist, therapy continues until normalization of “liver samples” +2 weeks.

In all trimesters of pregnancy, therapy is continued under the condition of monitoring the dynamics - a decrease in the activity of indicators of hepatic cytolysis or adequate therapy is prescribed when they increase.

After discharge from the hospital, an active transfer of the patient to the clinic at the place of residence is required to continue treatment and dynamic monitoring. In the future, a checkup by a gastroenterologist is mandatory to exclude chronic drug hepatitis, autoimmune hepatitis, primary biliary cirrhosis, hepatosis and biliary pathology due to the high frequency of manifestation of these diseases in women who have experienced drug hepatitis after childbirth.

Example 1

Patient P., 25 years old, was treated in the gynecology department with a diagnosis of Pregnancy 19-20 weeks, the threat of termination of pregnancy, mild anemia, and therefore received treatment: chimes, drotaverin, pentoxifylline, riboxin, sorbifer. Against the background of the treatment, an increase in hepatic cytolysis was recorded: ALT 138 U / L, ACT 91.7 U / L. Serological markers of viral hepatitis and autoimmune liver diseases are negative. Diagnosed with drug hepatitis with minimal activity. Ademethionine treatment was prescribed at a dose of 400 mg / day IV No. 7 with the abolition of previous therapy. On the 6th day of treatment, hepatic transaminase indices returned to normal and upon completion of the parenteral course of treatment, the patient was transferred to oral administration of ademetionine at a dose of 1600 mg / day with a treatment course of 1 month. Over the subsequent periods of pregnancy, weekly dynamic monitoring of biochemical parameters, an increase in hepatic transaminases was not detected. Delivery was carried out ahead of schedule in a natural way for a period of 36-37 weeks due to premature discharge of amniotic fluid. The condition of the newborn is satisfactory, weight 2950 g. After discharge from the perinatal center, the patient was actively transferred under observation to the clinic at the place of residence.

Example 2

Patient R., 27 years old, second pregnancy, 20-21 weeks. Received in the perinatal center with complaints of weakness, fatigue. From the anamnesis: 3 weeks before hospitalization, the patient suffered acute bronchitis, and therefore received outpatient treatment with ceftriaxone and paracetamol. Against the background of the treatment, the symptoms of bronchitis stopped, but weakness, fatigue persisted, and an increase in hepatic transaminases was diagnosed: ALT 238 U / L, ACT 221 U / L, alkaline phosphatase 390 U / L, and therefore a female consultation was sent for hospitalization in the Republican Perinatal Center . An objective examination of the patient's body weight of 65 kg, the skin is pale pink, the liver is not enlarged. Viral and autoimmune etiology of liver damage are excluded. The patient denied bad habits. Ultrasound of the liver did not reveal abnormalities. Diagnosed with moderate hepatitis and prescribed treatment: ademetionin 800 mg / day iv No. 10 + ursodeoxycholic acid 750 mg / day. Against the background of the therapy, the activity of serum transaminases and alkaline phosphatase returned to normal on the 11th day of treatment. The patient was discharged in satisfactory condition with recommendations to continue treatment with ademetionine 1600 mg / day orally + ursodeoxycholic acid 750 mg / day for 1 month, under weekly monitoring of blood biochemical parameters. Over the subsequent pregnancy, a repeated increase in transaminase levels was not detected. Delivery was carried out naturally at 39 weeks of gestation. The condition of the newborn was regarded as satisfactory, body weight was 3500 g. After discharge from the perinatal center, the patient was actively transferred under observation to the clinic at the place of residence.

Example 3

Patient N., 30 years old, consulted with a gestational age of 25-26 weeks in connection with the appearance of icteric staining of the sclera and a 10-12-fold increase in the activity of serum ALT and ACT, a 2-fold increase in the level of alkaline phosphatase and GGT. Subsequently, moderate hyperbilirubinemia due to both fractions of bilirubin was noted. Complaints during examination did not show. Subjectively, the condition was regarded as satisfactory, scleral ictericity was noted, sensitivity during palpation in the right hypochondrium, the liver protruded 2-3 cm from under the edge of the right costal arch, a dense consistency, smooth, rounded edge. The viral nature (antibodies to hepatitis A, B, C, D, E, cytomegalovirus, Epstein-Barr virus, herpes simplex) liver pathology was excluded. There were no serum markers of autoimmune hepatitis, Wilson-Konovalov disease, hyper-γ-globulinemia. The use of alcohol and drugs was denied. As a result, the disease is regarded as drug-induced hepatitis with high activity against the background of prolonged use of a combination of drugs (multivitamin-mineral complexes, iron, iodine, calcium with DZ, magnesium with B6). Pregnancy in a woman was the first, desired, the previous 2 pregnancies ended in abortion.

Due to the high activity of cytolysis, intravenous prednisone 90 mg / day was prescribed in combination with ursodeoxycholic acid (ursosan) 750 mg / day and ademetionine (heptral) 800 mg / day iv 10, then 1600 mg / day orally) . On the 5th day of therapy, there was a tendency to stabilization, and then to a decrease in the activity of serum transaminases, which allowed to prolong the pregnancy and continue treatment with a gradual decrease in the dose of prednisone. During subsequent dynamic observation, indicators of hepatic cytolysis gradually decreased, although they did not fully normalize at the time of delivery. Delivery was performed at the 38th week of pregnancy by cesarean section (according to obstetric indications) under epidural anesthesia. There were no complications in the postoperative period. In the postpartum period, the patient continued treatment with ademetionine at a dose of 1600 mg / day and ursodeoxycholic acid 750 mg / day. After a week, the activity of serum transaminases completely normalized, after which the course of treatment continued on an outpatient basis for up to 1 month, followed by drug withdrawal. During treatment, breastfeeding was not performed.

Example 4

Patient S., 25 years old, pregnant by the in vitro fertilization program (first pregnancy), was admitted to the republican perinatal center for a period of 31-32 weeks with complaints of itching of the skin within 3-4 days, weakness. During pregnancy, the patient took duphaston, utrozhestan, elevit pronatal, fenyuls, calcemin. An objective examination: the patient's body weight is 66 kg, the visible mucous membranes and skin are of physiological color, the liver is not enlarged. Biochemical blood test: ACT 60.7 U / L, ALT 64.3 U / L, alkaline phosphatase 470 U / L, GGTP 75 U / L, total bilirubin 21.62 µmol / L, (direct 15.89 µmol / L, indirect 5.43 μmol / L). Serological markers of viral hepatitis and autoimmune liver diseases are negative. Denied previous liver diseases, alcohol and drug use, had no contact with toxic substances. An increase in transaminases was detected for the first time. Ultrasound of the liver did not reveal abnormalities. Diagnosed with minimal active drug hepatitis. All previous drug therapy was canceled and treatment with ademetionine 800 mg / day iv No. 10 and ursodeoxycholic acid 750 mg / day was prescribed. Within 4 days, the itching stopped. Transaminase levels returned to normal on day 9. On the 12th day of hospitalization, the patient was discharged and outpatient treatment was prescribed - ademetionin orally 1600 mg / day and ursodeoxycholic acid 750 mg / day for two weeks, with weekly dynamic monitoring of hepatic cytolysis. An increase in transaminases in subsequent pregnancy was not observed. Delivery was carried out naturally for a period of 39 weeks. The condition of the newborn is regarded as satisfactory.

Example 5

Patient K., 33 years old, 4th pregnancy, 2nd birth, was admitted to the republican perinatal center for a period of 35-36 weeks with complaints of itching of the skin for 2 weeks, mainly at night, weakness, sleep disturbance . From the anamnesis: these complaints appeared after treatment in a day hospital due to utero-placental insufficiency by intravenous administration of pentoxifylline, actovegin and riboxin. The cancellation of these drugs, the appointment of suprastin and activated charcoal did not bring any effect, an increase in serum transaminases was recorded above 5 norms, and therefore was transferred to the perinatal center. An objective examination: the body weight of the patient is 74 kg, the skin is pale pink, the liver is not enlarged. Biochemical blood test: ALT 193 U / L, ACT 569 U / L, alkaline phosphatase - 507 U / L, total bilirubin - 16.1 mmol / L, direct 13.3 mmol / L, indirect 2.8 μmol / L. Ultrasound of the liver: diffuse changes in the liver parenchyma. The viral, autoimmune nature of hepatitis has been ruled out. Diagnosed with: Medicinal hepatitis with a cholestatic component, moderate activity. The treatment was prescribed: ademetionine 800 mg / day IV 10, ursodeoxycholic acid 1000 mg / day and IV prednisolone 90 mg / day. During therapy, itching stopped on the 5th day, transaminase activity less than 5 norms was recorded on the 7th day, and therefore, after a gradual decrease in dose, prednisone was completely canceled. By the time of delivery at the 38th week, transaminases were completely normal. Delivery is conducted through the natural paths. The condition of the newborn girl is satisfactory, body weight 3280 g. In the postpartum period in a hospital, and then outpatient treatment with ademetionine was continued orally at 1600 mg / day and ursodeoxycholic acid 750 mg / day for up to 1 month under the control of "liver tests".

Example 6

Patient M., 28 years old, pregnancy 31-32 weeks, first, male twins, after the in vitro fertilization procedure. The beginning of pregnancy was preceded by therapy with duphaston, utrozhestan, elevat pronatal, while taking them for a period of 10-11 weeks, an increase in ALT was recorded to 85 U / L, ACT to 76 U / L. The viral, autoimmune nature of liver damage was ruled out. According to the ultrasound of the abdominal organs, no deviations were detected. A diagnosis of drug-induced hepatitis with minimal activity was made, and therefore duphaston and the vitamin complex were canceled, and utrozhestan was prescribed intravaginally. The eslidine therapy was carried out in 2 capsules 3 times a day for a month. Against the background of the therapy, the activity indicators of serum transaminases returned to normal. At the end of the second trimester, the patient developed mild anemia, for which fenules were prescribed and at the age of 31 weeks of pregnancy the patient developed itchy skin, mainly at night. A biochemical blood test again revealed an increase in ALT activity to 521 U / L, ACT to 498 U / L, alkaline phosphatase activity increased by 1.5 times, GGTP - 5 times from the upper limit of normal. Hospitalized in the republican perinatal center. At the time of hospitalization, the patient's body weight was 70 kg. The viral and autoimmune etiology of hepatitis were excluded. According to abdominal ultrasound, moderate hepatomegaly, diffuse changes in the parenchyma of the liver and pancreas, thickening of the walls of the gallbladder up to 4 mm, signs of biliary sludge. Hepatitis expressed activity was diagnosed. Ursodeoxycholic acid was treated with 1000 mg / day, ademetionine 800 mg / day iv, prednisolone iv 120 mg / day. On the 3rd day of treatment, the level of serum transaminases stabilized, and from the 7th day began to decline, which allowed to gradually reduce the dose of prednisolone. Delivery was performed by caesarean section for a period of 37 weeks under epidural anesthesia. The operation went without complications. The mass of one of the newborns was 2700 g, the other 2350 g. Their condition was rated as satisfactory. In the postpartum period, treatment of the woman continued in the hospital with ademetionine orally at a dose of 1600 mg / day and ursodeoxycholic acid 750 mg / day, and then on an outpatient basis. The activity of serum transaminases fully normalized after 3 weeks.

Thus, the proposed method allows timely diagnosis of drug-induced hepatitis in pregnant women and an adequate, differentiated by the duration of pregnancy and the degree of severity of hepatic cytolysis drug therapy aimed at stopping the pathological process in the liver and preventing pregnancy complications. For this, drug therapy with hepatoprotectors and glucocorticosteroids, differentiated by gestational age and hepatic cytolysis activity, is used, which is fundamentally important for practical use in the clinic.

Claims (1)

A method of treatment and management tactics for pregnant women with drug hepatitis, which consists in the fact that, after a diagnosis of drug hepatitis is established, transaminases are performed in the 1st trimester with an asymptomatic increase in the range of 3 norms and there are no contraindications, plant-derived hepatoprotectors Carsil or Hepabene or essential phospholipids without vitamins are taken orally eslidine per os or essential forte N iv, per os in standard doses when other drug therapy is canceled, in the 2nd trimester at the level of serum nsaminases up to 5 norms orally take ademethionine 400 mg IV 7-10, then per os 1600 mg / day, treatment for 1 month, with serum transaminases from 5 to 10 norms - ademetionine 800 mg iv 10 N ursodeoxycholic acid 12 mg / kg / day, with a serum transaminase level of more than 10 norms, amedethionine 800 mg / day iv / ursodeoxycholic acid 12 mg / kg / day + prednisolone iv 90 mg / day, in the 3rd trimester at serum transaminases up to 5 norms orally take ademethionine 800 mg / day iv N10 + ursodeoxycholic acid 13 mg / kg / day, with transaminases from 5 to 10 norms - ademethionine 800 mg / day iv + ursodeoxycholic acid 13 mg / kg / day + prednisolone iv 90 mg / day, with progressive increase in serum transaminases over 10 norms during therapy with ademethionine 800 mg / day iv, ursodeoxycholic acid 13 mg / kg / day, intravenous prednisone 120 mg / day with the expectation of no more than 3 days, a decrease in the level of transaminases or their stabilization; therapy continues under the condition of monitoring dynamics - indicators of hepatic cytolysis - decreasing indicators of hepatic cytolysis or appropriate - when they increase, and in the postpartum period, therapy is continued in full until the normalization of “liver samples”.