Dynamics of markers of intrahepatic cholestasis in patients with primary biliary cholangitis when applying an integrated protein-amino acid and vitamin product (mare’s milk) Текст научной статьи по специальности «Клиническая медицина»

Received: 09 August 2019 / / Accepted: 03 September 2019 / Published online: 30 October 2019 UDC 616.361-002

DYNAMICS OF MARKERS OF INTRAHEPATIC CHOLESTASIS IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS WHEN APPLYING AN INTEGRATED PROTEIN-AMINO ACID AND VITAMIN PRODUCT (MARE'S MILK)

Maya S. Zhumabayeva1, https://orcid.org/0000-0002-2632-6717 Gulmira S. Dossatayeva1, https://orcid.org/0000-0003-4226-3741 Galiya M. Shaimardanova1, https://orcid.org/0000-0002-1414-8618 Larissa V. Kozina1, https://orcid.org/0000-0002-0581-6231 Viktor A. Tkachev2, https://orcid.org/0000-0003-4455-3427

1 JSC "National Scientific Medical Center", Nur-Sultan city, Republic of Kazakhstan;

2 NJSC "Medical University of Astana", Department of Propaedeutics of Internal Diseases, Nur-Sultan city, Republic of Kazakhstan.

Abstract

Introduction: Primary biliary cholangitis (PBC), formerly primary biliary cirrhosis, is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies (AMA) and characteristic histology. For 30 yearsursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. PBC is associated with the development of end-stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%-40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments.In way of the search for a safe and effective treatment for PBC mares milk acquires high potential in terms of affecting one of the links in the pathogenesis of PBC by modeling the composition of the intestinal microbiome. The intestinal microbiome plays an important role in the pathogenesis of PBC by regulating bile acid metabolism and immune responses.

The aim of the study - to evaluate the effect of a complex protein-amino acid and vitamin product (mares milk) on the indicators of markers of intrahepatic cholestasis in patients with PBC (primary endpoint).

Material and methods of the study. From September 2018 to the present time, an interventional non-randomised clinical trial (identifier NCT03665519) has been conducted in National Scientific Medical Center and currently, 23 patients have completed the study. Inclusion criteria: Patients with verified diagnosis of PBC, aged 18 to 75 years. Exclusion criteria: alcohol and/or drug dependence, presence of liver cirrhosis class C based on Child Pugh classification, allergic reaction to dairy products, pesence of mental diseases, severe concomitant pathology, regnancy and/or lactation, lactose intolerance. Participants from experimental (main) group were administered a supplement (sublimated mare milk 40 g/day) for 3 months accompanied with standard UDCA therapy (dosage of 15/kg/day). PBC patients from control group were administered only UDCA therapy (dosage of 15/kg/day). Markers of intrahepatic cholestasis were evaluated: gamma-glutamyltranspeptidase (GGT) and alkaline phosphatase (ALP) at the beginning of the study and after 3 months in patients of both groups.

Comparison of the dynamics between the groups was carried out in the context of visits using the one-way analysis of variance based on the Fisher criterion and the non-parametric Kruskal-Wallis test.

The level of statistical significance in the comparative analysis was adopted at 0.95 (a = 0.95). It means the expected level of reliability, statistical significance, at which the null hypothesis of the absence of statistical differences in the comparative analysis is rejected, should be less than 0.05 (p <0.05).

The results of the study. In patients of the main group, the level of ALP was significantly reduced to 6,72 ± 0,632 compared with the observation in the control group (9,30 ± 1,553). Comparing the dynamic level of GGTP in patients of the main group, this indicator was significantly reduced to 3.88 ± 0.611 compared with the control group (5.53 ± 0.770). The study showed a significant decrease in the main markers of intrahepatic cholestasis in patients with complex protein-protein and vitamin product (mare's milk).

The conclusion: The study showed a significant decrease in the main markers of intrahepatic cholestasis in patients after taking complex protein-amino acid and vitamin product (mares milk). Thus, the use of mares milk is an effective addition to the standard therapy of PBC.

Key words: primary biliary cholangitis, cholestasis, microbiome, mares milk.

Резюме

ДИНАМИКА МАРКЕРОВ ИНТРАГЕПАТИЧЕСКОГО ХОЛЕСТАЗА У ПАЦИЕНТОВ С ПЕРВИЧНЫМ БИЛИАРНЫМ ХОЛАНГИТОМ ПРИ ПРИМЕНЕНИИ КОМПЛЕКСНОГО ПРОТЕИН-АМИНОКИСЛОТНОГО И ВИТАМИННОГО ПРОДУКТА (САУМАЛ)

Майя С. Жумабаева 1, https://orcid.org/0000-0002-2632-6717 Гульмира С. Досатаева 1, https://orcid.org/0000-0003-4226-3741 Галия М. Шаймарданова 1, https://orcid.org/0000-0002-1414-8618 Лариса В. Козина 1, https://orcid.org/0000-0002-0581-6231 Виктор В. Ткачев 2, https://orcid.org/0000-0003-4455-3427

1 АО «Национальный научный медицинский центр», г. Нур-Султан, Республика Казахстан;

2 НАО «Медицинский Университет Астана», Кафедра пропедевтики внутренних болезней, г. Нур-Султан, Республика Казахстан

Актуальность. Первичный билиарный холангит (ПБХ), известный ранее как первичный билиарный цирроз - это редкое прогрессирующее холестатическое заболевание печени, отличительными признаками которого являются повышенный уровень щелочной фосфатазы, обнаружение антимитохондриальных антител (АМА) и характерная гистологическая картина. В течение почти 30 лет урсодезоксихолевая кислота (УДХК), является единственным доступным терапевтическим средством. ПБХ связан с развитием терминальной стадии заболевания печени (цирроза), повышенной заболеваемостью и смертностью. Было показано, что УДХК улучшает биохимические показатели, гистологическую картину и задерживает необходимость трансплантации печени. Клиническая проблема заключается в том, что приблизительно 25-40% пациентов не реагируют на стандартную терапию УДХК. В последние годы во многих исследованиях были исследованы альтернативные и дополнительные методы лечения. В свете поиска безопасного и эффективного метода лечения кобылье молоко приобретает высокий потенциал в плане воздействия на одно из звеньев патогенеза ПБХ путем моделирования композиции кишечного микробиома. Микробиом кишечника играет важную роль в этиопатогенезе ПБХ путем регулирования метаболизма желчных кислот и иммунных реакций.

Цель данного исследования: оценить влияние комплексного белково-аминокислотного и витаминного продукта (кобыльего молока) на показатели маркеров внутрипеченочного холестаза у больных с ПБХ.

Материалы и методы исследования: с сентября 2018 года по настоящее время на базе Национального научного медицинского центра проводится экспериментальное нерандомизированное клиническое исследование (clinicaltrials.gov identifier NCT03665519), Критериями включения были возраст от 18 лет, наличие верифицированного диагноза ПБХ, согласие на участие в исследовании. Критерии исключения: алкогольная и наркотическая зависимость, наличие цирроза печени класс С по Чайлд-Пью, наличие известной аллергии на молочные продукты, психические заболевания, тяжелая сопутстующая патология, беременность и/или лактация, непереносимость лактозы. В настоящее время завершили исследование 23 пациента (14 - из основной группы, 9 -из контрольной группы). Основную группу составили 14 человек, пациенты этой группы в дополнение к стандартной терапии (препараты урсодезоксихолевой кислоты) в течение 3 месяцев употребляли белково-аминокислотный и витаминный продукт (сублимированное кобылье молоко, разведенное в воде) в дозе 40 г в сутки. В контрольную группу вошли 9 человек, участники этой группы получали только стандартную терапию ПБХ. Оценивались маркеры внутрипеченочного холестаза: гамма-глютамилтранспептидаза (ГГТП) и щелочная фосфатаза (ЩФ) в начале исследования и через 3 месяца у пациентов обеих групп.

Сравнение динамики между группами проводилось в контексте визитов с использованием одностороннего дисперсионного анализа на основе критерия Фишера и непараметрического критерия Крускала-Уоллиса.

Уровень статистической значимости в сравнительном анализе был принят на уровне 0,95 (а = 0,95). Это означает, что ожидаемый уровень достоверности, статистической значимости, при котором отвергается нулевая гипотеза об отсутствии статистических различий в сравнительном анализе, должен быть менее 0,05 (р < 0,05).

Результаты исследования: у пациентов основной группы уровень ЩФ был достоверно снижен до 6,72 ± 0,632 по сравнению с наблюдением в контрольной группе (9,30 ± 1,553). Сравнивая динамику уровня ГГТП, у пациентов основной группы данный показатель был достоверно снижен до 3,88 ± 0,611 по сравнению с группой контроля (5,53 ± 0,770). Исследование показало достоверное снижение основных маркеров внутрипеченочного холестаза у пациентов на фоне приема комплексного белково-аминокислотного и витаминного продукта (кобылье молоко).

Выводы: таким образом, применение сублимированного кобыльего молока может стать эффективным многообещающим дополнением к стандартной терапии ПБХ.

Ключевые слова: первичный желчный холангит, холестаз, микробиом, кобылье молоко.

Тушндеме

Б1Р1НШ1Л1К БИЛИАРЛЫ ХОЛАНГИТКЕ ШАЛДЫККАН НАУКАСТАРДЫН ПРОТЕИН-АМИН КЫШКЫЛДЫ ВИТАМИН 9Н1М1 (САУМАЛ) КОЛДАНУДАГЫ ИНТРАГЕПАТИКАЛЫК ХОЛЕСТАЗ МАРКЕРЛЕР1Н1Н ДИНАМИКАСЫ

Майя С. Жумабаева 1, https://orcid.org/0000-0002-2632-6717 Гульмира С. Досатаева 1, https://orcid.org/0000-0003-4226-3741 Галия М. Шаймарданова 1, https://orcid.org/0000-0002-1414-8618 Лариса В. Козина 1, https://orcid.org/0000-0002-0581-6231 Виктор В. Ткачев 2, https://orcid.org/0000-0003-4455-3427

1 АК «¥лттык гылыми медициналык орталык», Нур-Султан к-, Казакстан Республикасы;

2 lшкi аурулар пропедевтика кафедрасы, КеАК «Астана Медициналык университет», Нур-Султан к-, Казакстан Республикасы.

бзектшт. Бурын бастапкы билиарлы цирроз ретЫде белгiлi бiрiншiлiк билиарлы холангит агзада сiлтiлiк фосфатаза декгейiнiк жогарылауы, антимитохондриялык антиденелердi (АМА) аныкталуы, сондай - ак сэйкес гистологиялык керУспен ерекшеленетiн бауырдыщ сирек прогрессивтi холестатикалык ауруы болып табылады. 30 жылга жуык уакыт бойы урсодеоксикол кышкылы жалгыз кол жетiмдi емдiк агент болып келдг Бiрiншiлiк биллиарлы холангит бауыр ауруыныщ (цирроз), сатылы аурудьщ жэне елiмнiн жогарылауымен байланысты. Урсодеоксил кышкылы биохимиялык параметрлердi, гистологиялык керУст жаксартып, бауыр трансплантациясыныщ кажеттiлiгiн кешЫретУ керсетiлдi. Клиникалык мэселе - наукастардыщ шамамен 25-40% -ына урсодексил кышкылымен жYргiзiлетiн стандартты терапия 8серi болмайды. Со^ы жылдары кептеген зерттеулер балама жэне косымша терапияны зерттедк Емдеудщ кауiпсiз жэне тиiмдi эдюн iздестiру кезiнде саумалмен емдеу шек микробиомыныщ курамын модельдеу аркылы бiрiншiлiк биллиарлы холангит патогенезiндегi байланыстардыщ бiрiне эсер ету тургысынан Yлкен элеуетке ие болады. 1шек микробиомы ет кышкылдарыныщ метаболизмi мен иммундык реакцияларды реттей отырып, бiрiншiлiк биллиарлы холангит этиопатогенезЫде ма^ызды рел аткарады.

Зерттеудщ максаты: кYPделi акуыз-амин кышкылы мен витаминдк енiмнiн (саумал) бiрiншiлiк биллиарлы холангитпен ауыратын наукастардагы бауырiшiлiк холестаздыщ керсеткiштерiне 8серiн багалау.

Зерттеу материалдары мен эдiстерi: Клиникалык сынак (clinicaltrials.gov identifier NCT03665519) 2018 жылдыщ кыр^йепнен казiргi уакытка дейiн ¥лттык гылыми медициналык орталык негiзiнде жYргiзiлдi, зерттеуге 18 жаска толган зерттеу шарттарымен толык танысып, руксаттама алынган наукастар iрiктелiп алынды. Шыгару критерийлерi: алкогольге жэне есiрткiге т8уелдiлiк, Child-Pugh сэйкес С тобындагы бауыр циррозыныщ болуы, сут енiмдерiне белгiлi аллергия, психикалык ауру, ауыр патология, жYктiлiк жэне / немесе лактация, лактозага тезбеушУк. ^рп уакытта 23 наукас зерттеудi аяктады (негiзгi топтан 14, бакылау тобынан 9). Негiзгi топ 14 адамнан турды, осы топтыщ пациент^ стандартты терапиядан баска (урсодеоксил кышкылына арналган препараттар) 3 ай бойы ^нЫе 40 г дозада акуыз-амин кышкылы мен витаминдi енiмдi (сублимацияланган саумал, ) тутынды. Бакылау тобы 9 адамнан турды, осы топтыщ катысушылары тек бiрiншiлiк билиарлы холангит Yшiн стандартты терапияны алды. ЖYрекiшiлiк холестаздыщ белгiлерi багаланды: гамма-глутамилтранспептидаза (GGTP) жэне сiлтiлi фосфатаза (ALP) зерттеу басында жэне 3 айдан кешн екi топтыщ наукастары.

Топтар арасындагы динамиканы салыстыру Фишер сынагы жэне параметрлi емес Крускал-Уоллис сынагы непанде дисперсияны бiр жакты талдауды колдана отырып бiрнеше келулер уакытында ЖYPгiзiлдi.

Салыстырмалы талдауда статистикалык мацыздылык децгей 0,95 (а = 0.95) децгешнде кабылданды. Б^л салыстырмалы анализде статистикалык айырмашылыктар жок деген болжам болган сенiмдiлiктiн, статистикалык мацыздылык денгейi 0,05-тен (p < 0.05) кем болуы керек дегендi бiлдiредi.

Зерттеу нэтижелерк негiзгi топтагы наукастар (6,72 ± 0,632) сiлтiлi фосфатаза дечгейiн бакылау тобындагы нэтижелермен салыстырганда (9.30 ± 1.553) ед8уiр темендедi. ГГТП де^гейУч динамикасын салыстыра отырып, негiзгi топтагы емделушiлерде бул керсеткiш бакылау тобымен (5.53 ± 0.770) салыстырганда 3,88 ± 0,611 дейiне азайды. Зерттеу кYPделi акуыз-амин кышкылды витаминдiк еым (саумал) бар емделушiлерде iшiлiк холестаздыщ негiзгi керсетюштерУч айтарлыктай темендегенiн керсетп.

Корытынды: Сонымен, сублимирленген саумалды колдану бiрiншiлiк биллиарлы холангиттщ стандартты терапиясына тиiмдi жэне перспективалы косымша емдеу эдю бола алады.

Нег '1зг '1 свздер: бiрiншiлiк билиарлы холангит, холестаз, микробиом, саумал.

Библиографическая ссылка:

Жумабаева М.С., Досатаева Г.С., Шаймарданова Г.М., Козина Л.В., Ткачев В.В. Динамика маркеров интрагепатического холестаза у пациентов с первичным билиарным холангитом при применении интегрированного протеин-амино-кислотного и витаминного продукта (саумал) // Наука и Здравоохранение. 2019. 5 (Т.21). С. 110-115.

7ЬитаЬауеуа M.S., Dossatayeva G.S., Shaimardanova G.M., Kozina L.V., Tkachev V.V. Dynamics of markers of intrahepaticcholestasis in patients with primary biliary cholangitis when applying an integrated protein-amino acid and vitamin product (mare's milk) // Nauka iZdravookhranenie [Science & Healthcare]. 2019, (Vol.21) 5, pp. 110-115.

Жумабаева М.С., Досатаева Г.С., Шаймарданова Г.М., Козина Л.В., Ткачев В.В. Бiрiншiлiк биллиарлык холангитке шалдыккан наукастардыщ комплексты протеин-амин кышкылды витамин eнiмi (саумал) колданудагы интрагепатикалык холестаз маркерлерЫщ динамикасы // Гылым жэне Денсаулык сактау. 2019. 5 (Т.21). Б. 110-115.

Background

Primary biliary cholangitis (PBC), formerly primary biliary cirrhosis, is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies (AMA) and characteristic histology. The prevalence of PBC in different countries varies and ranges from 40 to 400 cases of the disease per 1 million people; the highest values are recorded in northern Europe. Over the past decade, in some western regions, the prevalence of PBC has increased to 1 case per 700 people, a similar trend is observed in Kazakhstan.In the structure of mortality from cirrhosis of the liver of all types, the proportion of PBC is approximately 2% [1, 6, 7].

The results of studies carried out in the last 30 years made it possible to distinguish two main aspects of the etiology and pathogenesis of PBC - a genetic predisposition and trigger environmental factors [2,8].

Due to the lack of etiotropic therapy for PBC, the only justified pathogenetic treatment from the point of view of evidence-based medicine is the long-term, almost lifetime use of ursodeoxycholic acid. Treatment of patients with PBC with immunosuppressive drugs is ineffective or insufficiently effective.Taking the fact into consideration, that PBC is a slowly progressing disease, this ultimately leads to the need for liver transplantation [1, 3, 4].

However, liver transplantation is available only to a small percentage of patients due to the widespread deficiency of donor organs and the high cost of the procedure itself, the risk of complications associated with major surgery.

Despite improved survival with standard therapy, about 30% of patients with PBC show a lack of response to therapy and a poor prognosis. Orientation to the relationship between the exchange of bile acids and intestinal microbiome offers new perspectives for the treatment of PBC [5].

In way of the search for a safe and effective treatment for PBC mares milk acquires high potential in terms of affecting one of the links in the pathogenesis of PBC by modeling the composition of the intestinal microbiome. The intestinal microbiome plays an important role in the pathogenesis of PBC by regulating bile acid metabolism and immune responses.

The aim. To evaluate the effect of a complex protein-amino acid and vitamin product (mares milk) on the indicators of markers of intrahepatic cholestasis in patients with PBC.

Material and methods of the study.

From September 2018 to the present time, an interventional non-randomised clinical trial (clinicaltrials.gov identifier NCT03665519) has been conducted at the National Scientific Medical Center and currently, 23 patients with PBC have completed the study. All patients were recruited from the outpatient clinic of National Scientific Medical Center.

Inclusion ^iteria: Patients with verified diagnosis of PBC, aged 18 to 75 years. The diagnosis of PBC was based on the following three criteria:

1. biochemical evidence of cholestasis (elevation of alkaline phosphatase (ALP) in serum);

2. a positive test for AMA;

3. a liver biopsy with histological evidence of non-suppurative destructive cholangitis and destruction of interlobular bile ducts. Patients who met at least two of the three criteria were included in the study.

Exclusion criteria: alcohol and/or drug dependence, presence of liver cirrhosis class C based on Child Pugh classification, allergic reaction to dairy products, pesence of mental diseases, severe concomitant pathology, regnancy and/or lactation, lactose intolerance.

All patients voluntarily participated in the study, informed consent was signed. The protocol of this study was reviewed and approved by the Local Bioethics Commission. National Scientific Medical Center, Nur-Sultan city, Republic of Kazakhstan. Protocol №051/CT-29.

The age of the patients ranged from 22 to 55 years, the average age was 46.1. The participants are divided into 2 groups. The main group consisted of 14 people; in addition to standard therapy (ursodeoxycholic acid UCDA 15 mg/kg), patients in this group consumed a protein-amino acid and vitamin product (freeze-dried sublimated mares milk, diluted in water) at a dose of 40 g per day during 3 months.

The control group included 9 people; participants in this group received only standard therapy for PBC (ursodeoxycholic acid UCDA 15 mg/kg). Participants from both groups underwent analysis before and after 3 months. Markers of intrahepatic cholestasis were evaluated: gamma-glutamyltranspeptidase (GGT) and alkaline phosphatase (ALP) at the beginning of the study and after 3 months in patients of both groups.

Data processing and research were carried out using analysis of variance based on the Fisher criterion - the F-criterion, and the nonparametric method using the Kruskal-Wallis criterion. The statistical significance of the intragroup

dynamics in the groups of patients — the control and the main, from the time factor — the visit number of patient visits was evaluated.

The level of statistical significance in the comparative analysis was adopted at 0.95 (a = 0.95). It means the expected level of reliability, statistical significance, at which the null hypothesis of the absence of statistical differences in the comparative analysis is rejected, should be less than 0.05 (p <0.05).

Processing was carried out using software products:

• MicrosoftExcel spreadsheet editor for generating tabular data and primary processing of materials, calculating descriptive statistics;

• specialized software StatSoftSTATISTICAforWindows version 6.1 for conducting in-depth statistical analysis, group comparison, building histograms and span diagrams of medium and median.

Descriptive statistics for the main group, visit number 1.

• Comparison of the dynamics between the groups was carried out in the context of visits using the one-way analysis of variance based on the Fisher criterion - the F-criterion and the non-parametric Kruskal-Wallis test.

The results of the study

In patients of the main group, the level of alkaline phosphatase was significantly reduced to 6.72 ± 0.632 compared with the observation in the control group (9.30 ± 1.553). Comparing the dynamics of the gGt level, in the patients of the main group, this indicator was significantly reduced to 3.88 ± 0.611 compared with the control group (5.53 ± 0.770). Thus, in the main group compared with the control group, a statistically significant dynamics was observed in the studied laboratory indicators of cholestasis.

Below are tables with descriptive statistics (Tables 1-5).

Table 1.

Confidence Interval for Medium

№ Indicator n Average + standard error Standard deviation Median

-95% +95%

1 GGT 14 5,98 ± 1,056 4,479 3,755 8,210 4,32

2 ALP 14 8,20 ± 0,858 3,638 6,389 10,008 6,81

Table 2.

Descriptive statistics for the core group, visit number 2._

Confidencelnterval for Medium

№ Indicator n Average + standard error Standard deviation Median

-95% +95%

1 GGT 14 3,88 ± 0,611 2,287 2,557 5,199 3,43

2 ALP 14 6,72 ± 0,632 2,363 5,357 8,086 6,48

Table 3.

Descriptive statistics for the control group, visit number 1._

Confidence Interval for Medium

№ Indicator n Average + standard error Standard deviation Median

-95% +95%

1 GGT 9 6,22 ± 0,803 3,408 4,527 7,917 5,56

2 ALP 9 8,95 ± 1,147 4,866 6,532 11,371 7,77

Table 4.

Descriptive statistics for the control group, visit number 2.

Confidence Interval for Medium

№ Indicator n Average + standard error Standard deviation Median

-95% +95%

1 GGT 9 5,53 ± 0,770 2,309 3,752 7,301 6,35

2 ALP 9 9,30 ± 1,553 4,660 5,721 12,884 7,56

Table 5.

A summary table of the results of the assessment of the visit dynamics between the main and control groups using the Kruskal-Wallis test and the Fisher dispersion test (F-test)._

Indicator № visits Degrees of freedom Kruskal-Wallis test P Degrees of freedom F-test P

GGT Visit 1 (1;36) 0,4414 0,5064 (1;34) 0,0327 0,8575

Visit 2 (1;23) 2,8929 0,0890 (1;21) 2,8260 0,1076

ALP Visit 1 (1;36) 0,1001 0,7517 (1;34) 0,2763 0,6025

Visit 2 (1;23) 2,0992 0,1474 (1;21) 3,1113 0,0923

As can be seen from figures No. 1, 2 in the main group there was a significant decrease in cholestasis indicators -GGT, ALP.

Discussion

The studied biochemical markers - ALP and GGT - are early markers of cholestasis for establishing the diagnosis of PBC, and are also the main validated indicators for assessing the effectiveness of UDCA therapy and

stratifying the risk of disease progression. There are various criteria for evaluating the response to UDCA (Paris, Barcelona, msterdam, Toronto, etc.), but this was not part of the research objectives [4]. Initially, patients with PBC at various stages of the disease (from early to advanced fibrosis) participated in the main and control groups, most of the patients took UDCA preparations for more than 2 years.

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1 2 N Visit Group: Main Group

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12 N Visit Group: Control Group

Figure 1. Diagram of the range of means in the context of visits for the GGT indicator

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1 2 N Visit Group: Main Group

12 N Visit Group: Control Group

Figure 2. Diagram of the range of average in the context of visits for the indicator ALP.

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12

10

The study showed a significant decrease in the main markers of intrahepatic cholestasis of ALP and GGT in patients of the main group while taking a complex protein-amino acid and vitamin product (mares milk) as compared with the control group.

In this case, a decrease in cholestasis can be caused not only by the choleretic and cholekinetic effects of the studied product (sublimated mares milk), but also by its indirect effect on the metabolism of bile acids through the intestinal microbiome, exerting a pre- and probiotic effect. According to preliminary data, the majority of patients in the main group who had signs of a constipation syndrome on the background of PBC showed stool normalization, which also influenced an improvement in the quality of life, however, the study of the influence of mares milk on microbiome continues in the framework of this clinical trial.

It is known that pruritus is also one of the main clinical indicators of cholestasis, much worsening the quality of life. This indicator was evaluated on an appropriate scale, but it should be remembered that pruritus is very difficult for an objective assessment. A detailed analysis of the mares milk influence on the intensity of itching (pruritus) and changes in the quality of life is beyond the scope of this study and will be the subject of study in future reports of this ongoing clinical trial (NCT03665519).

During the study, none of the patients in the main group showed any adverse effects while taking the product, and there was no deterioration in the condition and rapid progression (decompensation) of the PBC.

This clinical trial of using mares milk in PBC patients is conducted for the first time in Kazakhstan.

The conclusion. The biochemical response in the form of improved indicators of cholestasis markers (ALP and GGT) is the most validated tool for assessing the effectiveness of treatment of PBC. The study showed a significant decrease in the main markers of intrahepatic cholestasis in patients after taking complex protein-amino

acid and vitamin product (mares milk). Thus, the use of freeze-dried mares milk is an effective addition to the standard therapy of PBC.

Conflict of interest. The authors declare no conflict of interest in this paper.

Funding. This work was supported by the grant from the Ministry of education and science of Republic of Kazakhstan. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.

The research results were not published earlier in other publications.

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2. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis // Journal of Hepatology. 2017. Vol. 67. P. 145-172

3. Goldblatt J., Taylor P.J., Lipman T. et al. The true impact of fatigue in primary biliary cirrhosis: a population study // Gastroenterology. 2002. Vol. 122. P. 1235-1241.

4. Ivashkin V.T., Bueverov A.O. Autoimmune liver diseases in the practice of a clinician. 2011, Moskow, 112p.

5. Kaplan M.M., Gershwin M.E. Primary biliary cirrhosis // N. Engl. J. Med. 2005. Vol. 353, № 12. P. 12611273.

6. Leuschner U. Autoimmune liver disease and overlap syndrome. 2005, M., 174 p.

7. Sheptulina A.F., Maevskaya M.V., Ivashkin V.T. A critical assessment of the pathogenetic factors of primary biliary cirrhosis // Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2013. N3. P.39-48.

8. Younossi Z. M., Kiwi M.L., Boparai N. Cholestatic liver diseases and health-related quality of life // Am. J. Gastroenterol. 2000. Vol. 95. P. 497-502.

Contact Information:

Shaimardanova Galiya Masugutovna - doctor of medical sciences, Head of the Department of Pathomorphology, JSC

National Scientific Medical Center, Nur-Sultan, Republic of Kazakhstan.

Mailing address: Nur-Sultan, Republic of Kazakhstan, 42 Abylay Khan Avenue.

Phone: +77017299148, 8 (7172) 57-76-18

E-mail: [email protected]