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Gulyamov Nariman, Dolimov Tohirbek, Nazarov Elbek,
Research institute of epidemiology microbiology and infectiouse diseases E-mail: 4rgandalf@gmail.com
EVALUATION OF GCS APPLICATION IN THE TREATMENT OF VIRAL HEPATITIS
Abstract: Glucocorticosteroids (GCs)were applied for inhibition of superfluous inflammation activity of pathological process [13]. GCs have been used in the treatment of viral hepatitis (VH) since 1950th. Management of hormones in patients with infectious diseases and particularly viral hepatitis are going on since nearly very beginning of hormones discovery. The first papers about successful management of cortisone and adrenocorticotrophin in viral hepatitis emerged in the middle of the 20th century [H. Butt, M. Comfort; H. Rilkin, L. Marks, 1952; J. Roskampl, 1953; H. Colbert, Holland and al. 1956 (cited by Kassirsky), and that was before the identification of viral etiology of hepatitis A (S. Feinstone, 1973) [9]. B (M.E Bayer, B.S Blumberg) [1] andC (1989 Choo et al.1989 Kuo et al.) [4, 14] and D [1977 Rizzetto) [15].
Keywords: prednisone, GCs, cortisone, hormones, Hepatitis B, Hepatitis C, Hepatitis DCBG.
Some authors recorded the "striking effect" of hormones in the a low affinity form upon cleavage of its reactive centre loop by various treatment of patients. Butlater data accumulation opinions of scien- proteases, for example neutrophil elastaze [17]. The main function of tific society tended to be more moderate. CBG seems to be GCs transport since under normal conditions 80-
T. Ritis applied prednisone at the dose of 30 mg per day in 34 patients with viral hepatitis during 24 days. Group of comparison included 31 patients who received placebo. It was established that bilirubin, transaminases and aldolase indices in both groups didn't differ significantly as well as prednisone.Later prednisone was displaced with prednisolone [13].
Liver is an organ of great significance insynthesis of corticosteroid binding globulin (CBG), transcortin, which plays a crucial role in transport function for GCs. Usage of GCs in patients with hepatitis especially viral hepatitis is the problem of great interest for global hepatology.The inflammation is the result of complex and balanced orchestra from several pro and anti-inflammatory mediators, cytokines, free radicals, fatty acids and enzyme activation. All this complex triggers activation of inflammation process not only in local, but and in cells which circulate in peripheric blood [10].
GCs are like Kapellmeisterthat are playinga leading part in inflammatory response control.
Itis well known that deficiency and excess of hormones can bring to various Pathologiesfrom acute pancreatitis to Cushing syndrome [6; 19; 20].
It is known that the GCs ability to regulate the inflammatory response is strongly related with their availability on the site of inflammation. Tissue availability of GCs, namely the proportion of GCs binding by the receptor and carrying out a response, depends of its synthesis at adrenal gland [6], its binding to the CBG [22], as well as its activation or inhibition catalyzed locally by the intracellular activity of enzymes 110-HSD1 and 110-HSD2 [3; 12]
Transcortin is mainly synthesized in liver, and it could be also produced by placenta, kidney and adipose tissue [7; 18; 21]. Trans-cortin is the primary cortisol binding protein, which is capable of conformational changes from a high cortisol-binding affinity form to
90% of circulating cortisol is bound with high affinity to CBG, while only 10-15% binds with low affinity to albumin and the remaining 5-10% is known as "free cortisol" [8, 12]. In our clinical practice we observed patients with severe course of hepatitis with complications who had intensive inflammatory and cytolytic process in liver and we found out that application of GCs was inefficient. That was one of our purposes to understand the pathophysiology of that process.
In clinical review of Aberdin, Singer (2006) was shown that systematic review found 13 adequate trials of steroid therapy prior to interferon-a involving 790 patients [16] Pre-treatment with-steroids for four to six weeks showed improved clearance of infection markers such as hepatitis e antigen and hepatitis B DNA. However there were no differences in mortality, incidence of hepatitis B surface antigen, hepatitis B e antibody, liver histology, or quality of life. Adverse events were equally distributed. They concluded that steroidsshould not be used for pre-treatment of chronic hepatitis B.
The same authors in their review involving eightrandomised trials that examined GCs in chronic hepatitis C [2], showed the great heterphenicity of results but in general there was no effect on all-cause or liver-related mortality, virological response, biochemistry, or liver biopsy findings. One trial reported a significant reduction in side-effects of interferon with concurrent steroid use [11].
The purpose of our research was to study variations of GCs hormones levels and efficacy of their application in patients with severe course ofviral hepatitis to reduce the liver necrosis
Materials and methods: We studied 51 patients with severe course ofviral hepatitis B, C and D diagnosed by ELISA and PCR at the clinic ofResearch institute ofEpidemiology Microbiology and Infectiouse Diseases (REIMID) from January 2016 to March 2017.
Age ranged 28-68 (middle age 41.6), 66% were males and 34% females. We examined our patients with clinical, biochemical (ALT,
Section 3. Medical science
AST) immunological (antigen binding lymphocytes (ABL) specifically sensibilizedto liver parenchyma tissue) methods.
We also used ELISA method to detect the levels of CBG and cortisole in blood and cortisole levels of saliva of patients. Control group included 27 healthy individuals.
Statistical analysis was carriedout using the program MicrosoftExcel 2.
Results: According to the clinical examination of patients, a severe course of chronic viral hepatitis exacerbation was noted in all the patients. Biochemical studies showed that in patients the mean values ofALT and AST were 1.57 mmol/L and 0.78 mmol/L, it was 2,31 times as high as upper limits of normal values (Table 1).
Detection of ABL specifically sensitized to the liver tissueanti-gen showed that their percentage achieved 11.68% and were 5,8 time as high as normal values (Table 1). Biochemical and immunological indices testified the intensive processes of cytolysis and the pathological process activity in the liver. Clinical, Biochemical and immunological datademonstrated a severe course of the disease in all the patientsindicating the intensive processes of cytolysis and activity of the pathologic process.
The serum content of patients with severe viral hepatitis in the liver-synthesized transcortin protein was 32.0 ± 4.26 yg/ml, it was I
3.20 times asloweras in healthy individuals (105.22 ± 2.01 yg/Ml). This indicates a significant decrease in the protein- synthesizing function, in particular, the synthesis of transcortin in the liver against the background of a pronounced activity of the pathological process.
Transcortin in blood serum ofpatients with severe course ofvi-ral hepatitis amounted to 32,0 ± 4,26 mm/ma, which was 3,20 times as low as in healthy individuals (105,22 ± 2,01 mm/ma). It indicates thesignificant decrease of protein synthetizing function, in particular, transcortin synthesis in liver against the background of apro-nouncedactivityof pathological process.
In patients with severe viral hepatitis, the content of total cortisol in blood was increased to an average of 1284.3 ± 89.50 nm/l, which was f 2.04 times higher than the parameters of healthy individuals varying from 140 to 630 nm/l (Table 1). The free cortisol content in saliva was also increased by f 1.85 times and amounted to 12.8 ± 1.03 ng/ml against the upper normal value norm equal to 6.9ng/ml (Table 1).
So a significant decrease in the blood content of transcortin, an increase in total cortisol in the blood and free cortisol in saliva against the background of high intensity of cytolysis and pathological process in liver in the patients with severe course of viral hepatitis were observed.
Table 1. - Biochemical, immunological and hormonal status (by transcortin and cortisol of blood plasma and saliva) in patients with severe course of viral hepatitis
Indexes Healthy individuals (control) (n = 27) Patients with severe course (n = 51) Induction index or suppression index
Biochemical indices
ALTmmol/L Up to 0,68 1,57 T2,31
AST mmol/L Up to 0,45 0,78 T 1,73
Immunological index
ABL to liver antigens (%) Up to 2% 11,68% T5,84
Indices of Transcortin (CBG) and Cortisol
Transcortin in blood serum (mkg/ml) 105,22 ± 2,01 32,0 ± 4,26 |3,20
Cortisol in blood plasma (nm/l) 140-630 1284,3 ± 89,50 T2,04
Cortisol in saliva (ng/ml) 0,65-6,9 12,8 ± 1,03 T 1,85
Conclusion: Therapy with GCs didn't show statistically significant changes in transcortin and cortisol levels in blood plasma, and cortisol levels in saliva in patients with viral hepatitis A, B, C and D.
So GCs-therapy application may be consideredas double-edged sword in treatment of viral hepatitis. On the one sideGCs protect hepatocytes from superfluous aggression of immunocompetent cells
of the host, but on the other side immunosuppression contributes to progression of the infection.
Immunosuppression induced by GCs-therapy contributes to increase of viral load and in the presence of antiviralpreparations indications to GCs-therapy are very limited, for example, they can be applied in the cases with expressed autoimmune component.
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