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  • Pregnancy with autoimmune liver disease( hepatitis, cholangitis, cirrhosis) - Causes, symptoms and treatment. MF.

    Autoimmune liver diseases include autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, unclassifiable( atypical) diseases: autoimmune cholangitis, cryptogenic( idiopathic, seronegative) hepatitis and cirrhosis, cross-syndromes in combination, including viral hepatitis. The prevalence and incidence rates of autoimmune liver diseases are steadily increasing, including.in connection with the increase in the quality of diagnosis, and they are registered mainly in women of reproductive age. Symptoms of autoimmune liver diseases

    Symptoms are extremely diverse, non-specific and are determined by the variant of the course of the disease, which can be latent( absence of symptoms in the presence of laboratory changes), low-symptom( single symptoms that do not significantly affect the condition of patients), have a symptom-complex of acute hepatitis or manifest complicationsin the terminal stage of the disease.

    In all cases, differential diagnostics with viral hepatitis, metabolic pathology of the liver( alcoholic or non-alcoholic steatosis, steatohepatitis), liver damage in helminthic invasions( opisthorchiasis), Wilson-Konovalov's disease and hemochromatosis, liver cancer and cholangiocarcinoma, as well as with drug lesions of the liver. This explains the considerable volume of diagnostic studies assigned to patients with suspected liver disease.

    Diagnosis of autoimmune liver diseases

    It includes a general blood test, determination of total bilirubin and its fractions, cholesterol, total protein and protein fractions, AST, ALT, APG, GGTP, IgA, M, G, CEC, CRP,coagulogram, rheumatoid factor, LE cells, serum markers of viral hepatitis B, C, D, G, TT, CMV infection, Epstein-Barr virus, herpes simplex type 1 and type 2, uric acid, serum iron, OZSSS,ferritin, transferrin, ceruloplasmin, copper in blood and in daily urine, serum oncomarkers( -fetoprotein, CA19-9, CEA) and serological markers of autoimmune diseases of the liver. The latter include autoantibodies to cellular and subcellular structures: antinuclear antibodies( ANA), antimitochondrial antibodies( AMA), antibodies to pyruvate decarboxylase complex( AMA-M2), antibodies to smooth muscle cells( SMA), antibodies to liver microsomes or kidneys 1type( LKM1), antibodies to soluble hepatic antigen( SLA), antibodies to hepatic pancreatic antigen( LP), antibodies to the cytoplasm of neutrophils( ANCA), etc.

    Autoimmune liver diseases are likely in the presence of signs of liver damage regardless of previousanovlennogo diagnosis, includingchronic viral hepatitis, especially if they are combined with anemia, etc. cytopenia, a sharp increase in γ-globulins( IgG), autoimmune diseases, heredity in autoimmune pathology;with unmotivated increase in ALT, AST, AF, bilirubin, regardless of the severity of the changes;with a combination of hepatomegaly, splenomegaly with a lability of liver and spleen sizes;in the presence of arthralgias, esophageal veins( especially in the absence of ascites), the absence of encephalopathy in advanced liver cirrhosis, xanthoma and xanthellasm, skin itching, hyperpigmentation of the skin and other conditions associated with autoimmune liver damage.

    Many factors can initiate immunopathological processes in the liver, most often hepatitis A, B, C, measles, environmental factors, excessive UV irradiation( including in the solarium), drugs( hormonal contraceptives, diclofenac, ketoconazole, somehepatoprotectors, interferons, etc.).The probability of genetic susceptibility to autoimmune diseases of the liver is discussed, which is associated, in particular, with C4AQO and HLA alleles of haplotypes B8, B14, DR3, DR4, DW3.C4A gene is associated with the development of autoimmune hepatitis in younger patients, HLA DR3-positive patients are more prone to early and aggressive course of the disease with less sensitivity to drug treatment, HLA DR4-positive patients are more prone to extrahepatic manifestations of the disease.

    In a number of cases, autoimmune liver disease in women is diagnosed for the first time in connection with pregnancy. At the same time, data on the development and course of pregnancy in autoimmune liver damage, as well as their mutual influence, are extremely poor.

    It is reported that such diseases are accompanied by hypogonadism, resulting in the absence of ovulation, amenorrhea and a rare occurrence of pregnancy. Nevertheless, in practice, the violation of reproductive function in patients with autoimmune liver diseases is extremely rare, so in the early stages of the disease pregnancy is possible and it occurs more often than in the later stages. The possibility of the emergence and retention of pregnancy in women with autoimmune liver disease indicates the existence of natural mechanisms that suppress immunity and ensure in most cases a successful termination of pregnancy. Development and preservation of pregnancy is also possible due to adequately conducted treatment with correctly diagnosed and allowing a woman to plan pregnancy for the period of remission.

    Autoimmune hepatitis

    Autoimmune hepatitis is currently defined as non-resolvable, predominantly periportal hepatitis, which occurs with hypergammaglobulinemia, tissue autoantibodies and amenable to immunosuppressive therapy. There are 2( sometimes 3) types of autoimmune hepatitis. Type 1 is associated with high titles ANA and SMA.The term "AIG of the 1st type" replaced the former definitions "lupoid hepatitis" and "autoimmune chronic active hepatitis".Autoimmune hepatitis type 2 is characterized by the presence of LKM-1 antibodies directed against cytochrome P-450 11DG;begins more often in childhood, acutely, proceeds with a lot of extrahepatic manifestations;progresses to cirrhosis faster than hepatitis type 1( for 3 years, respectively, in 82 and 43% of patients).

    Options for autoimmune hepatitis:

    1. Malosymptomatic or asymptomatic, when an increase in ALT and AST is detected by chance.

    2. Acute onset of the disease with severe course until the development of fulminant hepatitis with the development of hepatic insufficiency( prognosis is worse in patients with acute onset of the disease in terms of acute viral hepatitis, with evidence of cholestasis, ascites, repeated episodes of acute hepatic encephalopathy).

    3. Autoimmune hepatitis with dominant extrahepatic manifestations( arthralgia( joint pain), polymyositis( muscle pains), lymphadenopathy, pneumonitis, pleurisy, pericarditis, myocarditis, fibrosing alveolitis, thyroiditis, glomerulonephritis, hemolytic anemia, thrombocytopenia, nodal erythema, etc..)

    Options with dominant extrahepatic manifestations:

    - Feverish, manifested by intermittent fever( subfebrile or febrile) in combination with extrahepatic manifestations and increased ESR.- - Arthralgic( arthralgia, myalgia, acute recurrent migrating polyarthritis involving large joints without their deformities, spine joints) with late development of jaundice.

    - Jaundice, which has to be differentiated from hepatitis A, B, E and especially C, in which antibodies in serum can appear long enough after the onset of the disease.

    - In the form of "masks" of systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, autoimmune thyroiditis, etc.

    Most often autoimmune hepatitis debuts with nonspecific symptoms - weakness, fatigue, anorexia( weight loss, lack of appetite), decreased efficiency, myalgia and arthralgia, fever to subfebrile digits, discomfort in the upper abdomen, mild jaundice of the skin and sclera, skin itching. Unlike viral hepatitis, the disease progresses, and within 1-6 months there are clear signs of autoimmune hepatitis.

    Symptoms of the advanced stage of autoimmune hepatitis are characterized by varying degrees of severity of asthenic syndrome, fever, progressive jaundice, hepatosplenomegaly, arthralgia, myalgia, gravity in the right hypochondrium, hemorrhagic rash that does not disappear when pressed and leaves behind brownish brown pigmentation, lupus and erythema nodosum,focal scleroderma, "vascular asterisks", palmar erythema, etc.

    Diagnostic criteria for autoimmune hepatitis are increasedthe activity of ALT, AST, GGTP in the blood serum, hyper-γ-globulinemia and an increase in IgG content> 1.5 times, an increase in ESR, liver biopsy data, a high titer of serological markers of autoimmune hepatitis( ANA, SMA and LKM-1( in titres not less than 1:80 in adults and 1:20 in children, but the antibody titer may fluctuate, and sometimes they disappear altogether, especially during treatment with glucocorticosteroids( GCS).)

    Pregnancy in patients with autoimmune hepatitis, especially with low activity of the process, is often encountered, since. This disease affects mostly young women. Amenorrhea and infertility is usually accompanied by only a high activity of the hepatic process. However, she does not rule out the development of a woman's pregnancy, since treatment with SCS alone or in combination with azathioprine leads to a remission of the disease, supported by low, rarely-medium doses of drugs, against which the reproductive function in women is restored. Effective treatment leads to a significant increase in the survival rate of patients with autoimmune hepatitis, even at the stage of cirrhosis, so that patients are able to conceive and give birth( often twice) throughout the course of the disease, incl.after liver transplantation.

    The course of pregnancy in patients with autoimmune hepatitis and the effect of pregnancy on the course of the disease have not yet been studied enough. Most researchers believe that pregnancy in patients with autoimmune hepatitis against a background of remission supported by GCS, incl.at the stage of compensated cirrhosis of the liver without signs of portal hypertension, does not pose a big risk for a woman and a fetus. Exacerbations of the disease during pregnancy are rare. Laboratory indicators during pregnancy are often improved, returning after childbirth to the level noted before pregnancy. At the same time, cases of significant worsening of the condition of the pregnant woman are described, requiring an increase in the dose of GCS.However, controlled studies were not conducted, and it is unclear what the deterioration of the condition was related to.

    With high activity of autoimmune hepatitis, uncorrectable SCS, the condition of the pregnant woman worsens, the main liver functions are disrupted, liver failure, gestosis, fetoplacental insufficiency, abnormal placenta detachment, bleeding in the postpartum and postpartum period are possible. Fetal pathology can be expressed in signs of intrauterine hypoxia, hypotrophy and prematurity due to placental insufficiency. The probability of fetal death in this case is quite high.

    The probability of exacerbation of autoimmune hepatitis exists usually in the first half of pregnancy or in the postpartum period( usually in the first 1-2 months).An exacerbation of the disease in the puerperium is observed in about half of the patients. Exacerbation during pregnancy is usually associated with an unrecognized active liver process prior to its development, but in this case, in the second half of pregnancy, the activity of autoimmune hepatitis is usually reduced, which allows to reduce the dose of GCS to the minimum effective.

    Normal completion of pregnancy is observed in most women with autoimmune hepatitis. Unfavorable outcomes of pregnancy are observed in a quarter of cases, including serious complications, which are probably related to the presence of antibodies to SLA / LP.The frequency of uncomplicated births as the liver disease progresses decreases. Conversely, the incidence of spontaneous abortion and intrauterine fetal death increases. In this connection, patients at the stage of cirrhosis should be offered interruption of pregnancy in its early stages( up to 12 weeks), although it can be preserved with the woman's insistence if cirrhosis of the liver is not accompanied by signs of decompensation and pronounced pituitary hypertension accompanied by a high risk of life-threateningbleeding( often develops in the second or early third trimester of pregnancy).Maternal mortality in these situations reaches 50-90%.

    High frequency of bleeding from the esophagus in pregnant women suffering from cirrhosis of the liver, but absolutely contraindicated for pregnancy only III degree of varicose veins of the esophagus, incl.with erosive-ulcerative esophagitis. When I and II degrees without the effects of esophagitis, pregnancy can be maintained, but the patients need endoscopic control throughout pregnancy. Since such control is unrealistic in most maternity facilities, the risk of prolonging pregnancy in the presence of varicose veins of the esophagus is extremely high. It should be borne in mind that in the second trimester even in healthy women, transient varicose veins of the esophagus and stomach can develop as a consequence of an increase in the volume of blood.

    Primary biliary cirrhosis

    Primary biliary cirrhosis is a chronic cholestatic granulomatous, inflammatory disease of the smallest bile ducts caused by autoimmune reactions leading to prolonged cholestasis and capable of progressing to cirrhosis. Primary biliary cirrhosis often combines with other autoimmune diseases - thyroiditis, CREST syndrome, Sjogren's syndrome, rheumatoid arthritis, scleroderma, SLE, lymphadenopathy, myasthenia, endocrine disorders( polyglandular insufficiency), as well as with hepatic insufficiency, portal hypertension, ulcer bleeding, carcinomaliver, osteoporosis, etc. The disease in most cases develops in women after 40 years, but it is possible and at an earlier age. In young women, the disease manifests by pruritus, usually in the II-III trimesters of pregnancy, but is usually regarded as intrahepatic cholestasis of pregnant women( VCB).Diagnosis of primary biliary cirrhosis becomes possible much later, with the progression of symptoms, which often occurs with repeated pregnancies or taking oral hormonal contraceptives.

    There are 4 stages in the development of primary biliary cirrhosis. Stage 1 - the initial stage( stage of inflammation), characterized by lymphoplasmic infiltration of portal tracts, destruction of the epithelium of the bile ducts and basal membrane. At the 2 nd stage( progressive inflammation) portal tracts expand, periportal fibrosis develops, periportal foci of inflammation are detected, proliferation of small bile ducts occurs. In the third stage( septal fibrosis), signs of an active inflammatory process, parenchyma necrosis, portal tracts are emptied and replaced with scar tissue. The fourth stage is characterized by the formation of liver cirrhosis and its complications - regeneration nodes appear, inflammation foci of varying severity are detected.

    Typical symptoms of primary biliary cirrhosis include weakness, pruritus, cholestatic jaundice, hepatosplenomegaly, bone pain, muscle and hyperpigmentation of the skin, xanthelasm. At late stages, ascites and varicose veins of the esophagus are added. The primary biliary cirrhosis is characterized by an increase in serum AC activity 2-6 times or more, GGTP, cholesterol, bile acids, IgM( in 75% of cases), titer( more than 1:40, 1: 160) AMA, AMA-M2( in 95% of cases), which often correlate with PBC activity, can be detected at the preclinical stage and do not disappear throughout the period of the disease. There is a moderate elevated bilirubin content, a decrease in the prothrombin index, hypocalcemia( due to impaired absorption of vitamin D).Cases of AMA-negative PBC under the name of autoimmune cholangiopathy are described.

    Differential diagnosis of primary biliary cirrhosis is performed with obstruction of extrahepatic bile ducts, cholestasis caused by drugs( in these cases, AMA is absent, and withdrawal of drugs most often leads to the reverse development of the process), cholangiocarcinoma, primary sclerosing cholangitis and autoimmune hepatitis, sarcoidosis, biliary cirrhosiswith cystic fibrosis. The development of primary biliary cirrhosis in women is stimulated by estrogens, which are produced in the sex glands, adrenal glands, mammary glands, and during pregnancy - additionally in the fetoplacental unit. That is why primary biliary cirrhosis often manifests by skin itching during pregnancy.

    Data on the effect of primary biliary cirrhosis on the course of pregnancy are few and contradictory. In most studies, the increase in cholestasis due to primary biliary cirrhosis during pregnancy is associated with a risk of miscarriage and stillbirth;the functional state of the liver during pregnancy worsens. Data are provided that timely delivery in such patients is observed only in 30% of cases;16% of patients with primary biliary cirrhosis require abortion due to medical conditions. With the accumulation of clinical data on the impact of primary biliary cirrhosis on pregnancy, and also with the improvement of diagnosis of the disease in the early stages, when the functional state of the liver is still not significantly disturbed, and complications are absent, there are data that the pregnancy develops and safely terminates in 80%women with primary biliary cirrhosis, and spontaneous miscarriages occur in only 5% of pregnant women.

    In previous years, the prevailing view of the adverse effect of pregnancy on the course of primary biliary cirrhosis. The data of some authors indicate that in patients in the early stages of primary biliary cirrhosis, a short-term increase in serum markers of cholestasis and mesenchymal inflammatory syndrome is noted at the beginning of pregnancy. In the future, all indicators are normalized even without any treatment, remaining so throughout pregnancy. According to other data, the course of the disease worsens in the late stages of pregnancy. There was also information about the positive effect of pregnancy on the course of primary biliary cirrhosis. The possibility of the latter is explained by the fact that pregnancy, in which fetal rejection is physiologically prevented by natural immunosuppression, can have an immunomodulatory effect in an autoimmune disease, such as primary biliary cirrhosis. Immediately after birth, laboratory indicators of functional liver disorders in patients with primary biliary cirrhosis may increase, but for several weeks gradually decrease, returning to the baseline level observed before pregnancy. Postnatal increase in laboratory indicators is not usually associated with any symptoms.

    Delivery in patients with primary biliary cirrhosis can occur naturally. Only with a significant impairment of the functional state of the liver during pregnancy is the delivery performed by caesarean section.

    Primary sclerosing cholangitis

    Primary sclerosing cholangitis usually develops at a young age, incl.in 30-40% of cases - in women. It is characterized by a progressive fibrotic inflammation of the outside and intrahepatic bile ducts, leading to biliary cirrhosis. Disease in 70% of cases is combined with ulcerative colitis, less often - with Crohn's disease. The main signs of primary sclerosing cholangitis are pruritus, jaundice, cholangitis, marked weakness and rapid fatigue. Diagnostic criteria - ERHPG, contrast CT, MRI, liver biopsy, but all of them are contraindicated during pregnancy. In most cases, the disease is diagnosed before the age of 40, so many women are of childbearing age. Pregnancy in patients with primary sclerosing cholangitis is possible in the early stages of the disease and may even lead to an improvement in the functional state of the liver.

    In patients with primary sclerosing cholangitis, as well as with other autoimmune diseases of the liver, the prognosis for pregnancy is more favorable in its development in the early stages of the disease than in the later stages.

    Treatment of autoimmune liver diseases in pregnancy

    The basic drugs used to treat autoimmune liver diseases are immunosuppressive drugs, more often GCS, and ursodeoxycholic acid( UDCA).Other funds are used for strict indications. Specific drug therapy for autoimmune liver disease during pregnancy is not developed, so it is conducted according to generally accepted schemes.

    From non-pharmacological methods: it is necessary to avoid exposure to hepatotoxic substances, especially medicinal agents;physical exertion;overwork;hypothermia;psycho-traumatic situations;Physiotherapeutic procedures, especially on the liver region;should be 4-5 meals a day, exclude alcoholic beverages, fatty meats, fish, poultry, mushrooms, canned food, smoked products, chocolate. Favorable conditions for liver function as a result of increased hepatic blood flow create a bed rest.

    The main drug for the treatment of primary sclerosing cholangitis, incl.in pregnant women, is UDCA at a dose of 10-15 mg / kg body weight per day in 2-3 doses, which is also used to treat the syndrome of cholestasis in patients with primary sclerosing cholangitis, autoimmune hepatitis and cross-over syndrome. UDCA has a significant positive effect on the most important prognostic factors of primary sclerosing cholangitis - level of alkaline phosphatase, GGTP, transaminase, serum bilirubin, progression of histological changes, ascites and edema, as well as the severity of itching and general weakness;slows the progression of primary sclerosing cholangitis and positively affects the life expectancy of patients. The use of UDCA in the treatment of autoimmune liver diseases in pregnant women, according to the manufacturer's instructions, is allowed only in the last two terms. However, the drug can be used throughout the pregnancy, if an attempt to abolish it is accompanied by a sharp deterioration in the course of the disease. Undesirable side effects in newborns whose mothers took UDCA during pregnancy due to autoimmune liver disease are not described. On the other hand, it must be remembered that the highly teratogenic effect of UDCA drugs should be compared with the potentially negative effect on the fetus of hydrophobic bile acids and bilirubin, the level of which increases with cholestasis in the absence of UDCA therapy. It is in the early stages of pregnancy that the nervous system of the fetus is very susceptible to the effects of toxic substances.

    In the treatment of pregnant patients with primary sclerosing cholangitis and primary biliary cirrhosis, along with UDCA, enterosorbents, calcium preparations with D3 and detoxification therapy are used. To treat infectious complications in pregnant women with autoimmune liver diseases, especially for the treatment of primary sclerosing cholangitis, antibiotics from the penicillin and cephalosporins are used. Since pregnancy occurs with increased energy consumption, during treatment it is necessary to pay great attention to the nutrition of women - both enteral and parenteral. Starvation of pregnant women with liver disease is categorically contraindicated.

    In the treatment of autoimmune hepatitis, incl.in pregnant women, the main place belongs to the GCS.The American Association for the Study of Liver Disease( AASLD) proposed absolute( ACT≥ 10 N; AST55 N + γ-globulin ≥ 2 N; bridged or multicarine necrosis according to histological examination) and relative indications for their use in autoimmune hepatitis(fatigue, joint pain, jaundice) at the level of AST and γ-globulin & lt; absolute criteria).Treatment of SCS at the stage of inactive and decompensated liver cirrhosis, which has developed as a result of autoimmune liver diseases, is considered inexpedient. As criteria for the effectiveness of treatment of autoimmune hepatitis, the parameters of serum transaminases and γ-globulins are used. At the same time, it should be borne in mind that "biochemical remission" can precede the true( histological) remission for 3-6 months. Therefore, after the normalization of these indicators it is recommended to continue treatment for 6, and according to some data, 12 months. In patients who achieve remission, the dose of prednisolone is gradually reduced within 6 weeks.

    Forecast

    The accumulated experience indicates the relative safety of low and medium doses of GCS( within 30 mg of prednisolone per day) in pregnant women. Most women who receive SCS carry the pregnancy well. Only in some cases there is a transient increase in bilirubin and AP in the blood serum, which returns to the initial values ​​after childbirth. The prognosis for the fetus when using a pregnant GCS is considered more serious than for the mother. An increase in the incidence of spontaneous abortion and intrauterine fetal death is described, although it is difficult to relate these complications of pregnancy with the use of GCS.There is a low risk of fetal hypotrophy, slowing its growth, as well as giving birth to children with hard palate, especially when using high doses of glucocorticosteroids in the first trimester. However, the results of long-term follow-up of children born to mothers who receive SCS during pregnancy have been published, which did not show any deviations in the growth and development of these children. Despite the fact that SCS is absorbed into the blood, their use during lactation is also considered relatively safe.

    More and more work appears on the effectiveness of budesonide in the treatment of patients with autoimmune hepatitis, but its use in pregnant women is not described. As for azathioprine, during pregnancy, it is prescribed extremely cautiously, even in the presence of indications in the form of high activity of an autoimmune process not controlled by GCS.The experimental data do not completely exclude the teratogenic effects of the drug and the development of immunosuppression in newborns. Therefore, if a woman took azathioprine before the onset of pregnancy due to autoimmune hepatitis, during pregnancy it should be abolished whenever possible and can be used only in those rare cases when the disease is not controlled by adequate doses of SCS, there are contraindications to GCS, and from interruptionthe woman refuses categorically. If the abolition of azathioprine is associated with a high risk of worsening of the course of the disease, then its reception should be continued. In such cases, combined therapy with SCS is performed in the amount necessary to maintain remission of the disease. At the same time, it is assumed that the risk of intrauterine fetal development is less than the risk of recurrence of the disease in a pregnant woman.

    In the treatment of the "cross" autoimmune hepatitis / primary biliary cirrhosis( primary sclerosing cholangitis) a combination of prednisolone( from 20 mg / day) with UDCA( 13-15 mg / day) for a period of 3 to 6 months is used. Sometimes UDCA is appointed for life.

    Multiplicity and combinations of variants of liver damage, low specificity of symptoms, fundamental differences in the tactics of treating patients make the problem of timely diagnosis of autoimmune liver diseases extremely urgent. The result of untimely diagnosis is the beginning of treatment, the use of contraindicated drugs and, as a consequence, low life expectancy of patients. The early onset of proper treatment allows for remission and prevention of cirrhosis in autoimmune hepatitis, and in primary biliary cirrhosis and primary sclerosing cholangitis, improve quality, increase life expectancy, and avoid complications, including during pregnancy.