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Журнал "Здоров`я дитини" (62) 2015. Тематический выпуск "Детская гастроэнтерология"

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Department of Pediatric Gastroenterology and Nutrition

Автори: Babadzhanyan O.N.
Experience in the use urosodezoksiholevoy acid in children with organic diseases of the liver
Kharkiv meditsinskaya akademiya Postgraduate Education, Ukraine

Рубрики: Педіатрія/Неонатологія

Розділи: Клінічні дослідження

Версія для друку


The mechanism of action of ursodeoxycholic acid on the human body, the results of clinical studies and observations on the use of the drug ursodeoxycholic acid for the treatment of children with organic diseases of liver.

Ключові слова

ursodeoxycholic acid, children, organicheskime liver disease.

Among the many distinguished hepatic ursodeoxycholic acid - a physiological substance is approximately 1% of the human bile. UDCA treatment of diseases of the liver and biliary tract has an ancient history, more than 2,000 years ago in ancient China, doctors prescribed "liver" sick dry bear bile containing high concentrations of UDCA; in 1954 was described method for the synthesis of UDCA, and in 1975 - the action of UDCA on bile (bile desaturation, the dissolution of small cholesterol stones). Since that time, the drug began to be used for the treatment of gallstones, in the course of treatment, improvement was seen "liver" biochemical parameters, which was the basis of expansion of therapeutic possibilities of UDCA and its purpose in other liver diseases. Ursodeoxycholic acid is a nontoxic tertiary bile acid (BA), which is formed in the intestine and liver, normally contained in human bile in small quantities - less than 5% of the total pool of bile acids. It is more polar and hydrophilic in comparison to other LCD that causes its almost complete lack of toxicity. To date, well-known and tested numerous specific effects of UDCA: antiholestatichesky, choleretic, cyto / hepatoprotective, anti-apoptotic, immunomodulatory, cholesterol-lowering, litholytic, antifibrotic, anti-oxidant, anti-neoplastic. Receiving UDCA causes an increase in bactericidal and intestinal contents, bile, inhibition of bacterial growth in the intestines, arresting the fermentation and putrefactive dyspepsia has metabolic effect, contributing to a reduction in serum glucose, insulin, and HOMA index regulates lipid metabolism, homeostasis of bile acids, as well as proliferation and differentiation cholangiocytes. Thus, UDCA performs important functions and outside enterohepatic axis and acts as a systemic metabolic integrator. Range of pathological conditions of the liver is very large, and most of these changes may be accompanied by a violation of any of the functions of the liver or many with a particular predominance. It UDCA is the best drug for pathogenetic therapy of a wide spectrum of diseases of the liver and biliary tract to the impact on the maximum number of pathogenesis. Given the physiological role of UDCA its introduction from the outside is the preferred therapeutic decisions from the first days of the disease, probably at the stage of diagnostic search. It is important to bear in mind that in liver disease due to the global impairment of its functions can greatly disturbed metabolism of pharmaceuticals, followed by uncontrollable side effects. In this regard, such patients may use only shown completely and reliably safe drugs. The greatest positive experience gained UDCA us by using the drug Ursofalk®, Dr. Falk Pharma GmbH, Freiburg (since 1987). Currently, about 75% of children with liver disease Ursofalk get the recommended dosages, with about 10% - more than 10 years. Since 1987. We did not have a single case of intolerance Ursofalk, demanded his resignation.
It should be noted that we observed children with chronic viral hepatitis B and C (31 children) received no specific antiviral therapy for various reasons: the presence of contraindications, early age (up to 3 years), a large number of side effects of antiviral therapy, the failure of parents, lack of permission for assignment of pegylated interferons for children weighing less than 35 kg, and al. Treatment of children included diet and conservative mode, based multifactorial disease Ursofalk dose of 10-15 mg / kg body weight per day for three months courses one - twice a year during the entire period of observation. Children with chronic drug / toxic hepatitis were treated twice a year Ursofalk courses for three months at a dose of 10-15 mg / kg body weight for a long time - the duration accordingly appointed hepatotoxic drugs. Three girls with autoimmune hepatitis receiving immunosuppressive therapy with prednisolone, against this background, one girl gets Ursofalk for 13 months at a dose of 15 mg / kg body weight, one girl courses twice a year for three months against the background of long-term maintenance dose of prednisone at a dose of 15 mg / kg body weight, one - to continue the course Ursofalk twice a year for three months in a state of stable remission after discontinuation of prednisone for 2 years in doze10 mg / kg body weight. Children with a1 antitrypsin deficiency and child and Alagille syndrome in the complex therapy receiving prolonged courses of three months Ursofalk at a dose of 10-15 mg / kg body weight. All we observed children with congenital syndromes of intrahepatic cholestasis (Baylera disease, undifferentiated progressive familial intrahepatic cholestasis, non-syndromic form of hypoplasia of the bile ducts) were born full-term with anthropometric measurements, the normal physiological range. Jaundice appeared on the 2-3-5 day life. Approximately two-thirds of the patients showed the presence of "lucid intervals" - decrease in the intensity of jaundice by the end of 1-2 weeks of life, followed by a gradual rise and its greenish appearance of jaundice by the end of 1 month; Characteristic is the fickle nature of Ahola chair and no hepatomegaly at birth followed by an increase in liver size and change its consistency from elastic to solid during the first 2 months of life. By the age of 1-3 months of life developed hemorrhagic syndrome (bleeding from the mucous membranes of the digestive system, the umbilical wound, intracranial hemorrhage) caused by deficiency of vitamin K-dependent clotting factors resulting in malabsorption of vitamin K in the intestines. By the age of 1-2-4 months of life for all children observed was formed underweight, the severity of which depended on the type of infant feeding. The earliest sign of illness laboratory serves to increase at the expense of direct bilirubin in the serum fraction of greater than 20% of total bilirubin level, characterized by an increase in other biochemical markers of cholestasis (β-lipoproteins, cholesterol, alkaline phosphatase, bile acids, and others.), Severity which increases the dynamics of the minimum increase for the first 2-3 weeks of life to a significant increase to 2-3 months. Cytolytic enzymes (ALT, AST) rose moderately, and usually delayed. In most cases during the first 2-3 weeks after birth, these figures remained within the normal range and then gradually increases to reflect the protein-synthetic function of the liver (albumin, fibrinogen, PB et al.), In the early stages of the disease, have not changed. Of the two children from the same family with progressive familial intrahepatic cholestasis type I (disease Byler), under our supervision, a boy with severe pruritus, xanthomas to 6 months of life, there are signs of portal hypertension, splenomegaly, indicating that the formation of biliary cirrhosis , the manifestations of which in the future progressively narasli and from which in the age of 1,5 years old baby died. The second child - a girl of 10 months at the moment is on maintenance therapy, bile acid sequestrants and Ursofalk a dose of 25 mg / kg body weight and is preparing for liver transplantation. Three children with non-differentiable progressive familial intrahepatic cholestasis (in the process of diagnostic search) and a child with non-syndromic form of hypoplasia of the bile ducts receive maintenance therapy at a dose Ursofalk 20-25 mg / kg body weight permanently. Two girls from the same family, the disease begins with the first few weeks of intense jaundice with a high level of direct bilirubin and signs of deficiency of fat-soluble vitamins (bleeding due to a deficiency of vitamin K) during the observation noted undulating course jaundice, presence of a "lucid intervals" each time longer followed by a gradual increase in jaundice with bilirubin values each time lower than the previous one. Clinical features of the disease and the results of further examination allowed the girls to diagnose benign familial intrahepatic cholestasis caused by hypoplasia of the lymphatic vessels of the liver - Sammerskila syndrome. All children with cryptogenic hepatitis Ursofalk received from 3 to 6 months under the control of biochemical samples of the liver lasting from 1 year to 11 years. Two boys with ulcerative colitis, confirmed the results of histological examination, the clinical picture of the disease (from the first days of observation) dominated extraintestinal lesions - were expressed cytolysis and cholestasis syndromes. Both child ursofalk initially received a dose rate of 20 mg / kg body weight for 3 months, and then over the years, in a maintenance dose of 10 mg / kg for three months twice a year. When you try not to carry out maintenance therapy showed an increase in transaminase levels 2-3. One boy with ulcerative colitis in two years from the onset of the disease appeared cytolysis syndrome, which required the appointment Ursofalk at a dose of 12 mg / kg of body weight for three months. According to the testimony of children with cholestasis prescribed concomitant therapy, the correction of mitochondrial disorders vitamins B6 and E, correction and prevention of osteoporosis drugs calcium and vitamin D3, correction of deficiency of fat-soluble vitamins A, E and K.A very interesting observation - the only one in our long-term practice, the case is rare in children the disease - primary sclerosing cholangitis (PSC). The etiology of this disease is still not established. Some importance in the development of PSC can be toxic (hydrophobic and lipophilic) bile acids - lithocholic and deoxycholic coming into the liver through the portal vein from the intestine and can cause destruction of the ductal epithelium of the biliary tract with the accumulation of oxygen free radicals - products of lipid peroxidation, which "run "the process of caspase activation and increase of apoptosis of epithelial cells of the bile ducts. Most authors studying the PSC, see it as an autoimmune disease.We observed the boy with primary sclerosing cholangitis - to date the boy was 15 years old, sick 13 years, the disease debuted with subfebrile, itching of the skin, increasing the overall weakness. The boy was admitted to hospital where at inspection on the background hepatolienal syndrome revealed anemia, Dysproteinemia syndrome cytolysis diffuse changes in the liver tissue with ultrasound. Burdened family history - his father bronchial asthma; allergic history is not burdened, indications of surgery, blood transfusion, blood donation and the presence of comorbidities in the past is not. In a survey of the child were excluded: Vilsona-Konovalov disease, α1-antitrypsin deficiency, storage diseases, inherited disorders of amino acid metabolism, autoimmune hepatitis. According to the results of computerized tomography / in contrast revealed hepatosplenomegaly and focal liver changes of unspecified origin (neoplastic ?, inflammatory process?); histological examination of biopsy specimens of the liver occurs morphological pattern characteristic of chronic sclerosing cholangitis - described vanishing bile duct syndrome with periportal fibrosis and initial morphological features of cirrhotic changes. The research allowed to diagnose primary sclerosing cholangitis and begin treatment metipred 16 mg per day and Ursofalk 250 mg per day, which resulted in biochemical remission. After eight months of starting treatment due to lower doses of glucocorticoid drugs, the boy appeared loose stools up to five times a day, mixed with blood, in the endoscopic examination revealed erosion of the mucosa of the sigmoid colon, after the appointment salofalka and correction dose glucocorticosteroid drug (a return to the primary dose ) the boy's condition has improved. After ten months of the onset of the disease had increased transaminase levels that dictated the need for increasing doses Ursofalk to 25 mg / kg body weight. In this case, administration of UDCA was aimed not only pathogenic effect on the pathological process in the liver, but also taking into account data on the effect of UDCA on reducing the risk of colorectal dysplasia in patients with ulcerative colitis and primary sclerosing cholangitis, was meant to address the issue kantserpreventsii. After a month of therapy high-dose UDCA boy decreased cytolytic process in the liver - decreased levels of alanine aminotransferase and aspartate aminotransferase. A control study rektoromanoskopicheskoe - moderately expressed phenomena of catarrhal proctosigmoiditis, by histological examination of biopsy - manifestations of chronic colitis with limfofollikulyarnoy hyperplasia and partially atrophic changes that allowed the boy to put concomitant diagnosis - chronic non-specific non-ulcer colitis (atrophic), the period of partial clinical remission. To date, with a body weight of 63 kg boy continues to receive metipred 16 mg per day and Ursofalk 600 mg per day, in a state of biochemical remission. However, according to the literature, the treatment of PAF UDCA therapy does not affect the progression of fibrosis and inflammation in the liver, which are responsible for the destruction of the bile duct stenosis and with the appearance of a progressive ductal obstruction of the system and has no effect on survival.
Dynamic observation of children receiving UDCA allowed noted in almost all clinical and biochemical improvement.
For timely staging of fibrosis and control its development during treatment, as well as to assess the necroinflammatory liver tissue in a number of children was held FibroTest. The test shows the stage of fibrosis (F0, Fl, F2, F3, F4) and the degree of necroinflammatory (AO, Al, A2, A3) International standard system METAVIR, allows universalnuyu interpretation of research results. All of the children surveyed was determined significant decrease necroinflammatory and that seems to us important decrease in the progression of fibrosis - reduction of fibrosis stage. For example, reducing F3 to Fl boy with cryptogenic hepatitis Ursofalk gets a dose of 15 mg / kg body weight twice a year for three months for 2 years; decline from F0 to F2 boy with chronic hepatitis C with moderate activity and a high viral load is Ursofalk 15 mg / kg body weight twice a year for three months for 4 years. Thus, studies have shown a positive impact on the state Ursofalk children with liver disease; for the prevention of irreversible changes in the liver, and treatment of patients must be possible to start as soon as possible.
Author: Babadzhanyan Olena, Candidate medichnih Sciences, Associate Professor of Pediatric Gastroenterology and Nutrition KhMAPE. Address: Ukraine, Kharkov, ul.Derzhavinskaya 2-B, kv.49.
Phone: +380504009909

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