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AKTya&BHi npoSAeMH cynacHoi' MeAHUHHH
KHIHIHHA TA nPOOIHAKTMHHA МЕflMЦMНА
DOI 10.31718/2077-1096.22.1.4 UDC 616.36-085.616-035.1 Aghayeva S. Ch., Hidayatov A. A.
THE IMPACT OF OCCULT HEPATITIS B INFECTION ON THE COURSE OF CHRONIC HEPATITIS C TREATMENT WITH DIRECT-ACTING ANTIVIRALS
Azerbaijan Medical University, Baku, Azerbaijan
The prevalence of viral hepatitis B and C in Azerbaijan is 3.2% and 4.3% respectively. The incidence of occult hepatitis B has not been previously studied. The purpose of this study is to assess the prevalence of occult hepatitis B infection among patients with chronic hepatitis C, as well as to assess the impact of occult hepatitis B on the progression of liver disease and to identify the likelihood of viral/clinical reactivation of occult hepatitis B during treatment with direct-acting antiviral drugs. Results. The study included 164 patients with chronic hepatitis C with the absence of overt hepatitis B (HBsAg negative). A specific immunoglobulin to the core antigen of the hepatitis B virus (anti-HBcIgG) was examined and, depending on its serological activity, the patients were divided into 2 groups: 72 anti-HBcIgG-positive and 92 anti-HBcIgG-negative individuals. Hepatitis B Virus DNA was tested in both groups. During the treatment of hepatitis C with direct-acting antiviral drugs, the evidence of viral and clinical reactivation of occult hepatitis B was evaluated. Results. Out of 72 anti-HBc positive patients, 18 (25%) showed detectable viral load. None of the patients had a pre-treatment Hepatitis B Virus DNA level greater than 2000 IU/mL (34-223 IU/mL). Out of 92 anti-HBcIgG negative patients, none had positive Hepatitis B Virus DNA prior to the treatment. In the group of patients with chronic hepatitis C and positive anti-HBcIgG, clinical manifestations and changes in biochemical parameters were more pronounced that in anti-HBcIgG negative group, however, this correlation was not statistically significant. In both groups, there was no 1 log increase in Hepatitis B Virus DNA and ALT during and after the treatment. Conclusions. In Azerbaijan, the presence of anti-HBc IgG was observed in 43% of patients with chronic hepatitis C. In patients who are negative for anti-HBcIgG, 100% had undetectable Hepatitis B Virus DNA. Among those with positive anti-HBcIgG, 25% had low levels of Hepatitis B Virus DNA, which accounted for 10.9% of the total number of patients with chronic hepatitis C. Positive anti-HBcIgG was associated with higher pre-treatment ALT and liver fibrosis score. Treatment with direct-acting antiviral drugs did not cause virological or clinical reactivation of occult hepatitis B in both groups. The presence of OBH did not affect sustained virological response in the treatment of chronic hepatitis C.
Key words: hepatitis B, hepatitis C, Hepatitis C Virus, treatment.
Introduction
Hepatitis B infection is a global public health problem. About two billion people are considered infected, of which 250 million live with chronic Hepatitis B Virus (HBV) infection [1]. Mutations in the hepatitis B surface antigen result in strains not detectable by conventional HBsAg tests; however, anti-HBcIgG in serum may or may not be present. [2-6]. Occult hepatitis B (OHB) is defined as the presence of low-level HBV DNA in serum, cells of the lymphatic system and/or liver tissue of patients with serological markers of previous HBV infection (anti-HBc and/or anti-HBs) in the absence of serum HBsAg. More than 20 percent of patients have no serological markers and HBV DNA remains the only marker of HBV infection. Thus, depending on the presence of anti-HBcIgG and anti-HBs, OHB may be defined as seropositive or seronegative [7]. The diagnosis of OHB is based on polymerase chain reaction (PCR) and real-time PCR analysis [8]. Often, occult infection is defined by the presence of anti-HBcIgG with a negative anti-HBs test, as a result of lack the neutralizing effect of anti-HBs in
these individuals [9]. The prevalence of occult hepatitis B varies from 1 to 87 % in different geographical areas. The incidence correlates with the prevalence of chronic hepatitis B in the same region [10-11]. Mutations in the HBsAg gene have been observed in patients co-infected with hepatitis C virus [12-13]. About one third of patients with chronic hepatitis C infection have been shown to have HBV DNA with the absence of serum HBsAg
[14]. When the coexistence of HBV and Hepatitis C Virus (HCV) genomes occurs in the same hepatocyte, HBV replication is inhibited due to interference with HCV molecules, resulting in the formation of OHB with low HBV DNA replication
[15]. In addition, HCV core proteins NS2 and NS5A can strongly inhibit HBV replication [16-18].
On the territory of Azerbaijan from 2013 to 2016, 14,234 people were screened for the presence of HBsAg and anti-HCV. 1068 people were diagnosed with viral hepatitis (7.5 %). It was estimated that the prevalence of hepatitis B and C in Azerbaijan was 3.2 % and 4.3 % respectively.
The aim of our study is to define the prevalence of occult hepatitis B infection and the risk of
AKTya&BHÏ npoÖAeMH cynacHoï mcahuhhu
viral/clinical HBV reactivation in the treatment of HCV with direct-acting antivirals.
Materials and methods
This is a prospective study that included 164 (106 men, 58 women) patients with chronic hepatitis C, but negative HBsAg marker. Depending on the presence of anti-HBcIgG in serum, they were divided into two groups: positive and negative. Patient selection criteria included positive quantitative HCV DNA test, no or minimal degree of hepatosteatosis (grade I), (mean BMI 22.3 kg/m2);
alcohol withdrawal within the last 6 months or moderate use, negative autoimmune and other markers of liver disease; no previous treatment with nucleoside analogues. Because the national hepatitis B immunization program was launched in 2002, only patients who had not been routinely vaccinated were included in the study. Twenty-six patients (15.9%) had previously been treated with pegylated interferon (peg-IFN) and ribavirin (RBV) and were subdivided into non-responders and relapsers groups, as shown in Table 1.
Table 1
Prior HCV treatment and response pattern
Number of patients Untreated Peg- IFN and RBV used
Non-respondents Relapsers
Men 90 4 12
Women 48 2 8
Total 138 (84.1%) 26 (15.9%)
All patients received pan-oral DAA therapy from February 2016 to May 2017. We selected the most affordable treatment regimens in Azerbaijan, such as sofosbuvir / ledipasvir (± ribavirin) - 12 weeks for genotype 1 and sofosbuvir / daclatasvir (± ribavirin) - 12 weeks for genotype 2 and 3. Of the 164 patients, 11 received original direct-acting antiviral drugs (DAAs) (Harvoni, Sovaldi Gilead Science Inc., Daklinza Bristol-Myers Squibb); 153 patients received analogues from Indian and Egyptian manufacturers.
All patients were screened for HBsAg, anti-HCV, anti-HBs, anti-HBc IgM, anti-HBc IgG with commercially available ELISA assay kits (Acon, San Diego, CA, USA). HBV DNA and HCV RNA as well as HCV genotyping were determined using Abbott real-time PCR (sensitivity 12 IU/mL). Ultrasound and Fibroscan were performed to determine the stage of liver disease before treatment.
Depending on the serological activity of anti-HBc-IgG, patients were divided into 2 groups: Group I included 72 (43%) anti-HBc-IgG-positive (49 men and 23 women, mean age ± SD 47.5 ± 9.8 years).
Group II included 92 (56%) anti-HBc-IgG-negative patients with (57 men and 35 women, mean age ± SD 43.6 ± 12, 5 years).
HCV RNA, HBV DNA, ALT and AST were tested
before treatment, at the 2nd, 4th, 12th week of the treatment period, as well as at 4th, 12th and 24th weeks after end of treatment. Signs of virological /clinical reactivation of hepatitis B virus, such as an increase in HBV DNA and ALT levels, were monitored during and after the end of treatment. In accordance with the Declaration of Helsinki, the scientific work was approved by the ethics committee of the Azerbaijan Medical University and informed consent was obtained from all patients. Descriptive statistics were calculated for all variables. Demographic variables and qualitative data were analyzed using frequency tables and chi-squares. Independent samples were used to analyze the values of Fibroscan and ALT for patients with HBV/HCV co-infection, as well as with occult hepatitis with detectable and non-detectable viral load. The significance level was set at p = 0.05. All statistical analyzes were performed in SPSS 25.0.
Results
Of the 92 anti-HBcIgG negative patients, none had detectable HBV DNA. Out of 72 anti-HBcIgG positive patients, detectable HBV DNA was observed in 18 (25%). All 18 patients in this group were Anti-HBs negative. HBV DNA ranged between 12 and 2027 IU/mL and is displayed in Table 2.
Table 2
Its of quantitative analysis of HBV DNA in occult infection patients
Number of patients, total =18 HBV DNA (IU/ml)
5 10-100
4 101-500
4 501-1000
3 1001-2000
2 >2000
The overall mean fibrosis score was 8.3 kPa that correlates with FII fibrosis stage. The overall mean ALT level was 72 IU/L. In HCV patients with positive anti-HBc IgG with the presence of detectable HBV DNA, clinical manifestations of liver
disease, such as ALT and the degree of fibrosis, were more pronounced than in patients with negative anti-HBcIgG. The values of the indicators are displayed in Figure 1.
Tom 22, BunycK 1 (77)
5
AKTya&BHi npoSAeMH cynacHoi' MeAHUHHH
8
Figure l.the values of the indicators
There was no statistically significant difference between both groups in terms of age and gender (p > 0.005). The overall sustainable virologic response rate for HCV treatment was 98.7%. Two patients relapsed, however, none had evidence of HBV reactivation, such as an increase in ALT or an increase in HBV DNA. One relapsed patient previously treated with pegylated interferon and ribavirin, positive for anti-HBc IgG, negative for anti-HBs, negative for HBV DNA before and during the treatment. The second post-transplant patient relapsed 8 weeks after the end of treatment, negative for anti-HBc IgG and anti-HBs. None of the patients had a 1 log increase in HBV DNA or an increase of ALT during and after treatment.
Discussion
In the 1970s, a new clinical form of HBV infection was identified after acute hepatitis B infection in a patient after the blood transfusion from a donor with positive immunoglobulin G for the HBV core antigen (anti-HBc IgG) but negative HBsAg [2]. At the international EASL workshop in Italy (2008), OHB was defined as the detection of HBV DNA in the liver (with or without serum HBV DNA) without the presence of HBsAg [12]. The presence of mutations has been described in the pre-S1, pre-S2, and S regions of the HBsAg gene, leading to non-detection of HBsAg by standard enzyme immunoassays [3-6]. In patients with OHB, it was found that substitution of the 458 gene loci interferes with the splicing of the S gene mRNA and this causes a lack of HBsAg expression and low HBV DNA replication. The occurrence of the sG145R mutation in the "a" determinant of the HBsAg gene also leads to OHB [4]. The presence of anti-HBc antibodies in serum is an important clue for tracking OHB, although about 20% of all cases are also negative for anti-HBc antibodies. [9]. Viral load below 200 IU/ml has been defined to a cut-off value to diagnose OBH, but interestingly, more than 90% of patients with OHB have a serum viral load of about 20 IU/ml [10]. Since the presence of untreated OHB increases the risk of developing liver cancer both with and without HCV co-infection, timely diagnosis and treatment are essential to prevent further complications [19].
HBcIgG
of fibrosis and alt in hcv patients
Conclusion
In Azerbaijan, anti-HBc IgG is detected in 43% of patients with chronic hepatitis C patients. Detectable HBV DNA is observed in 25% of anti-HBcIgG-positive and 10.9% of the total number of patients with hepatitis C. None of the patients with negative anti-HBcIgG had detectable HBV DNA. The presence of anti-HBcIgG with detectable HBV DNA is associated with higher ALT and higher fibrosis scores in patients with HCV. Treatment with DAAs did not cause HBV reactivation. Overall SVR was not associated with the presence of occult hepatitis B.
Prospects for future medical research
Occult hepatitis B may be considered a hidden risk factor for reactivation of the virus under the condition of immunosuppression, as well as a predisposing factor of hepatocellular carcinoma. The development of highly sensitive assays for early detection, treatment and follow-up of the OHB may prevent complications in the future. Awareness of OBH may also contribute to the decreased transmission of the HBV from HBsAg-negative blood and organ donors.
References
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3. Raimondo G, Pollicino T, Romano L, Zanetti AR. A 2010 update on occult hepatitis B infection. Pathol Biol (Paris). 2010;58:254-257.
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7. Chen BF. Hepatitis B virus pre-S/S variants in liver diseases. World J Gastroenterol. 2018;24:1507-1520.
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9. Escobedo-Melendez G, Panduro A, Fierro NA, Roman S. High prevalence of occult hepatitis B virus genotype H infection among children with clinical hepatitis in west Mexico. Mem Inst Oswaldo Cruz. 2014; 109:728-737.
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12. Lelie N, Bruhn R, Busch M, et al. Detection of different categories
of hepatitis B virus (HBV) infection in a multi-regional study 17.
comparing the clinical sensitivity of hepatitis B surface antigen and HBV-DNA testing. Transfusion. 2017;57:24-35.
13. Candotti D, Lin CK, Belkhiri D, et al. Occult hepatitis B infection in 18. blood donors from South East Asia: molecular characterisation
and potential mechanisms of occurrence. Gut .2012;61:1744-1753.
14. Caviglia GP, Pellicano R, Saracco GM, Smedile A. Hepatitis B core-related antigen: a serum biomarker for intrahepatic 19. covalently-closed-circular DNA. Clin Lab. 2018;64:411-412.
Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017; 152: 1297-1309.
Macera M, Stanzione M, Messina V, et al. Interferon-free regimens in hepatitis B surface antigen/anti-hepatitis C virus patients: the need to control hepatitis B virus replication to avoid hepatitis B virus reactivation. Clin Gastroenterol Hepatol. 2017; 15: 1800-02. Coppola N, Onorato L, Pisaturo M, et al. Role of occult hepatitis B virus infection in chronic hepatitis C. World J Gastroenterol. 2015; 21: 11931-40.
Bersoff-Matcha SJ, Cao K, Jason M, et al. Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis c virus: a review of cases reported to the U.S. Food and Drug Administration Adverse Event Reporting System. Ann Intern Med. 2017; 166: 792-98.
Wong DK, Huang FY, Lai CL, Poon RT, Seto WK, Fung J, et al. Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma. Hepatology. 2011;54:829-836.
Реферат
ВЛИЯНИЕ ОККУЛЬТНОЙ ИНФЕКЦИИ ГЕПАТИТА Б НА ТЕЧЕНИЕ ЛЕЧЕНИЯ ХРОНИЧЕСКОГО ГЕПАТИТА С ПРОТИВОВИРУСНЫМИ ПРЕПАРАТАМИ ПРЯМОГО ДЕЙСТВИЯ Агаева С. Ч., Гидаятов А. А.
Ключевые слова: гепатит Б, гепатит С, вирус гепатита С, лечение.
Распространенность вирусных гепатитов Б и С в Азербайджане составляет 3,2% и 4,3% соответственно. Заболеваемость оккультным гепатитом Б ранее не изучалась. Целью данного исследования является оценка распространенности скрытой инфекции гепатита Б среди пациентов с хроническим гепатитом С, а также оценка влияния оккультного гепатита Б на прогрессирование заболевания печени и выявление вероятности вирусной/клинической реактивации оккультного гепатита Б при лечении противовирусными препаратами прямого действия. Объект и методы. Исследование включало 164 пациента с хроническим гепатитом С и отсутствием явного гепатита Б (отрицательный HbsAg). Был исследован специфический иммуноглобулин к ядерному антигену вируса гепатита Б (анти-НВс^) и в зависимости от его серологической активности, пациенты были разделены на 2 группы: 72 анти -НВс^-позитивных и 92 анти-НВс^-негативных пациентов. ДНК вирусного гепатита Б была исследована во обеих группах. При лечении гепатита С противовирусными препаратами прямого действия, были изучены свидетельства вирусной и клинической реактивации оккультного гепатита Б.
Результаты. Из 72 пациентов с положительным анти-НВс 18 (25%) имели обнаруживаемую вирусную нагрузку. Ни у одного из пациентов уровень ДНК вирусного гепатита Б до лечения не превышал 2000 МЕ/мл (34-223 МЕ/мл). Из 92 пациентов с отрицательным анти-НВс^, ни у одного не было обнаружено ДНК вирусного гепатита Б до лечения. В группе пациентов с хроническим гепатитом С и положительным анти-НВс^, клинические проявления и изменения в биохимических показателях были более выражены, но эта корреляция не была статистически значимой. В обеих группах не было выявлено 1 1од-увеличения ДНК вирусного гепатита Б и показателя АЛТ во время лечения и после него. Выводы. В Азербайджане наблюдается присутствие анти-НВс ^ в крови у 43% больных с хроническим гепатитом С. У пациентов с отрицательным показателем анти-НЬс^, 100% имели отрицательный ДНК вирусного гепатита Б. Среди лиц с положительным анти-НВс^, у 25% определялся низкий уровень ДНК вирусного гепатита Б, что составляло 10,9% от общего числа пациентов с хроническим гепатитом С. Позитивный анти-НВс^ сопровождался более высокими показателями АЛТ и более высоким показателем фиброза печени. Лечение с помощью противовирусных препаратов прямого действия не вызвало вирусологической или клинической реактивации оккультного гепатита Б в обеих группах. Наличие оккультного гепатита Б не влияло на устойчивых вирусологический ответ при лечении хронического гепатита С.
Реферат
ВПЛИВ ОКУЛЬТНО1 1НФЕКЦ11 ГЕПАТИТУ Б НА ПЕРЕБ1Г Л1КУВАННЯ ХРОН1ЧНОГО ГЕПАТИТУ С ПРОТИВ1РУСНИМИ ПРЕПАРАТАМИ ПРЯМО1 Д11 Агаева С. Ч., Пдаятов А. А.
Ключовi слова: гепатит Б, гепатит, вiрус гепатиту С, лкування.
Поширенють в1русних гепатит1в Б та С в Азербайджан! становить 3,2% та 4,3% вщповщно. Захво-рюванють на окультний гепатит Б рашше не вивчалася.
Метою даного дослщження стала оцшка поширеност прихованоТ шфекци гепатиту Б серед пац1ен-т1в з хроычним гепатитом С, а також оцшка впливу окультного гепатиту Б на прогресування захворю-вання печшки та виявлення ймов1рност1 в1русноТ/кл1н1чноТ реактивацп окультного гепатиту Б пщ час л1-кування против1русними препаратами прямоТ дм.
Об'ект та методи. В дослщжены прийняли участь 164 пац1енти з хрошчним гепатитом I вщсутнютю явного гепатиту Б (негативний HbsAg). Було дослщжено специф1чний 1муноглобул1н до ядерного антигену в1русу гепатиту Б (анти-НВс^), та залежно вщ його серолопчноТ активност пац1енти були роздн
Том 22, Випуск 1 (77)
7
лен1 на 2 групи: 72 анти-НВс^-позитивш та 92 анти-НВс^-негативш пац1енти. ДНК в1русного гепатиту Б була вивчена в обох групах. При л1куванн1 гепатиту С против1русними препаратами прямоТ д1Т були вивчен1 св1доцтва в1русноТ та кл1н1чноТ реактивац1Т окультного гепатиту Б. Результати. З 72 пац1е-нт1в з позитивним анти-НВс 18 (25%) мали в1русне навантаження. У жодного з пац1ент1в р1вень ДНК в1-русного гепатиту Б до л1кування не перевищував 2000 МО/мл (34-223 МО/мл). З 92 пац1ент1в з негати-вним анти-HВcIgG, у жодного не було виявлено ДНК в1русного гепатиту Б до л1кування. У груп1 пац1ен-т1в з хрошчним гепатитом С та позитивним анти-НВс^ кл1н1чн1 прояви та змши в б1ох1м1чних показни-ках були бтьш виражен1, але ця кореляц1я не була статистично значущою. В обох групах не було виявлено 1 1од-збтьшення ДНК в1русного гепатиту Б та показника АЛТ пщ час л1кування та пюля нього. Висновки. В Азербайджан! спостер1гаеться присутн1сть анти-НВс IgG в кров1 у 43% хворих з хрошчним гепатитом С. У пац1ент1в з негативним показником анти-НЬс^, 100% мали негативну ДНК в1русного гепатиту Б. Серед ос1б з позитивним анти-НВс^, у 25% визначався низький р1вень ДНК в1русного гепатиту Б, що становило 10,9% вщ загальноТ к1лькост1 пац1ент1в 1з хрон1чним гепатитом С. Позитивний анти-HBcIgG супроводжувався вищими показниками АЛТ та вищим показником ф1брозу печшки. Л1ку-вання за допомогою против1русних препарат1в прямоТ дм не викликало в1русолог1чноТ або ктшчноТ' ре-активац1Т окультного гепатиту Б в обох групах. Наявнють окультного гепатиту Б не впливало на стшку в1русолопчну в1дпов1дь при л1куванн1 хрон1чного гепатиту С.
DOI 10.31718/2077-1096.22.1.8
УДК 616.31-002:616.311.2-002:616.314.17-008
Березняков В. I.
КИСЛОТНО-ОСНОВНИЙ СТАН КРОВ1 ТА ЗМ1ШАНО1 СЛИНИ ПОРОЖНИНИ РОТА У ХВОРИХ НА НЕГОСПГГАЛЬНУ ПНЕВМОН1Ю ТА ЙОГО ЗНАЧЕННЯ В Д1АГНОСТИЦ1 ТА ПРОГНОЗУВАНН1 ЗАХВОРЮВАННЯ
Харшська медична академiя пюлядипломноТ ocBiTM
Порушення кислотно-лужного балансу е показником багатьох патолог'чних змн, як безпосередньо впливають в тому числi i при негоспталь^й пневмон'й. Мета роботи - вивчення кислотно-основного стану кровi та змшано)' слини у хворих, що страждають на негосптальну пневмоню при тестових навантаженнях та визначення ефективностi навантаження в дiагностицi захворю-вання. Матерiали та методи. Обстежено 34 дорослих хворих, що страждали на негосптальну пневмоню, як перебували в терапевтичному в'дд'тенш Мсько)' клiнiчно)'лiкарнi № 25 м. Харкова. Дi-агноз негосп'тально)' пневмон'й встановлювали на пдставi епiдемiологiчних, клiнiчних, лаборатор-них, рентгенологiчних даних. Вс показники пор1внювали iз даними групи практично здорових ос'б. Проведено пор!вняльне досл'дження динамки рН кровi i слини хворих, що страждають на негоспi-тальну пневмоню, а також концентрацИ кальцю i неорганiчного фосфату в змiшанiй слин при тестових загрузках. Виявлено тсний взаемозв'язок динамки досл'джуваних параметр'¡в як при цукро-вому, так i при карбам'дному навантаженн'1. Висновки. Основним д'агностичним показником порушення кислотно-основного стану кров'1 та слини хворих, що страждають на негосптальну пневмоню, е рН та надлишок чи деф/'цит основ. При цукровому навантаженн'1 у хворих, що страждають на негосптальну пневмоню, в'дбуваеться накопичення кислих екв'талент'т, зниження рН змшано)' слини, концентрацИ неорганiчного фосфату та пдвищення концентрацИ кальцю. При карбам'дно-му навантаженн фосфатна буферна система слини пдключаеться, переважно, для корекци КОС при значеннях рН нижче 6,0. oдержанi результати будуть сприяти оптим'зацИ д'агностики негос-птально)' пневмон'й.
Ключов1 слова: кислотно-лужний стан, негосгптальна пневможя, тестов1 навантаження.
Робота е фрагментом НДР «Мукоактивнi та рослиннi лжарсью засоби для лкування кашлю при гострих iнфекцiйно-запальних захворюваннях нижнiх дихальних шляхiв» № державно)'реестрацп 0117U000595.
Вступ
Пщтримка гомеостазу в порожниш рота за-лежить вщ стабшьносп життевих функцш оргаш-зму в цтому. Порушення кислотно-лужного балансу е показником багатьох патолопчних змш, як безпосередньо впливають на Тх стан [1, 2]. Вщ цього показника в кровi та порожниш рота залежать нейтралiзуючi та мiнералiзуючи влас-тивост слини, активнють ротовоТ мiкрофлори, градiент та швидкють юнообмшних процеав [3, 4]. Тому важливим е вивчення кислотно-лужного
стану не ттьки в кров1, а й в зм1шанш слин1 ротовоТ порожнини у хворих, що страждають на негосштальну пневмошю (НП).
Вщомо також, що мехашзм слиновидтення здшснюеться вегетативною нервовою системою - симпатичною та парасимпатичною - за участ ппоталамуса. Мед1атором симпатичноТ нервовоТ системи е норадреналш, а парасимпатичноТ -ацетилхолш. Встановлено, що активац1я симпатичноТ нервовоТ системи пригшчуе генерацш слини (в основному, водноТ частини). При цьому слини видтяеться дуже мало та вона в'язка. Ак-
