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Aziza Makhmudova, Äziza Azlarova, Dilorom Makhmudova, Inna Berger, Maya Makhmudova, Naima Ahrarova, Ozoda Madasheva Research Scientific Institute of Hematology and Blood Transfusion MoH of Uzbekistan Republic Uzbekistan, Tashkent E-mail: [email protected]
FUNCTIONAL CONDITIONS OF THE LIVER IN HEMOPHILIA PATIENTS INFECTED BY HEPATITIS B
Abstract: Viral infection is the most significant, but not the only factor affecting the functional state of the liver in patients with hemophilia. Multiple transfusion ofplasma, erythrocytes, cryoprecipitate from various donors leads to sensitization and autoimmune disorders. Posthemorrhagic anemia, unavoidable with frequently recurring bleeding in patients with hemophilia, leads to prolonged hypoxia of tissues, including hepatocytes. Keywords: hemophilia, hepatitis B, transfusion complications.
The modern level ofthe transfusion medicine development divided into 3 groups, depending on the results of detection is allowed to successfully solve the problems of hemorrhagic of HbsAg markers:
complications for hemophilia patients. However, the intensive Group 1: 13 HBsAg positive patients aged 10 to 29 years
haemostatic therapy may lead to high risk for transmission the viral hepatitis, which is associated with the frequent use of blood products, such as cryoprecipitate, fresh frozen plasma, that did not pass through the virusinactivation process.
According to various authors in different countries from 60 to 90% of hemophilia patients were infected with viral hepatitis, and about 80% of them had the liver function disorders [2,4,5,6]. The risk of the incidence of viral hepatitis among patients with hemophilia is in 16.7 higher than in the general population, and the death rate from liver diseases among hemophilia patients is 20% [6].
The liver damage in hemophilia patients can be caused by many factors — viral hepatitis, prolonged protein and im-munological overload, related with infusion and transfusion therapy and use of hepatotoxic drugs (antibiotics, sedatives, analgesics) [2,3].
The purpose of our study was: To study the influence of hepatitis B virus (HBsAg) infection on the liver functional condition of hemophilia patients.
Materials and methods. 117 patients with severe form of hemophilia A and B (with factor VIII content was 1.2 ± 0.3% and factor was IX 1.9 ± 0.2% respectively) were examined in the Department of Hemostasis of Scientific Research Institute of Hematology and Blood Transfusion. All patients were
(average age 22.4 ± 6.8 years),
Group 2: 89 HBsAg negative patients with positive serological results on HBcAg and anti-HBsAg isolated or combined, whose age varied from 4 to 39 years (averaging 19.6 ± 8.8 years).
Group 3: The control group consisted from 15 patients with hemophilia from 4 to 32 years old (average age 13.1 ± 9.5 years) with out any of the markers of the Hepatitis B virus.
All examined patients are male. Differences in age between groups were statistically not significant (p> 0.05)
The duration of transfusion of blood products did not differ significantly between the control group and groups of patients infected with HBV virus (p> 0.05), and was 10.6 ± 3.3 years in the control group, 19.8 ± 7.2 years and 15.6 ± 8.6 years in the 1st and 2nd groups, respectively.
Serological diagnosis of HBsAg, anti-HBs, anti-HBc antibodies was performed with commercial test systems "ELISA Diagnostic HBsAg, HBcAg, anti-HBs "NGO Diagnosticum" (Nizhny Novgorod). The genotype of hepatitis B virus in HBsAg positive samples was performed by the method of enzyme immunoassay by the systems "HBV genotype EIA" (Institute of Immunology Co. Tokyo, Japan).
In order to obtain optimal information, biochemical studies were carried out in dynamics from 3 to 6 times the patient's
Section 11. Medicine
examination. The choice of the studies spectrum was based on the use of the most informative tests, reflecting the state of functional liver systems using unified methods of laboratory research characterizing:
— protein synthetics (total protein, prothrombin index, fibrinogen)
— pigmentary disorders (bilirubin common with fractions), liver function
— cytolytic syndrome (ALT, AST).
Ultrasound examination of the hepatobiliary system was carried out by a Sonoskope-30 apparatus operating in real time.
Biopsy is the most reliable method, characterizing the morpho-functional status of the liver. Despite the high information content of such investigation, the risk of the possible complications in this procedure in hemophilia patients exceeds the diagnostic value. Therefore, we decided to refrain from this survey method.
Results. The data of serological testing showed 13 cases of positive carriage of HBsAg out of 117 patients (11.1%), antibodies were detected in 57 (48.7%), and in 102 (87.1%) cases were detected antibodies to the nuclear antigen (anti HBcAg). Only in 15 (12.8%) cases were not detected any of the markers of the hepatitis B virus.
Determination of the virus genotype in 13 serum samples of HBsAg positive patients revealed genotype D (100%) in all cases. This corresponds to the data of previous epidemiology studies ofviral hepatitis in Uzbekistan [7], where the genotype D ofthe HS virus is indicated as the most common cases (77%).
Infection with Hepatitis B depended on the duration of the transfusion anamnesis. In the 1st and 2nd groups, the duration of the blood products use was significantly longer than in the control group. There were not revealed a statistically significant difference in the biochemical and coagulogical parameters between the 1st and 2nd groups in comparison with the control group. Nevertheless, the following changes were detected in group 1: ALT increase by 1.2-2.5 times and ASTs 1.1-2 times higher than normal in 8 (61.5%) of virus-infected patients, in 6 (46, 1%) patients there was a moderate bilirubinemia from 21.3-34.9 ^mol / l, fluctuations in the level of total protein were associated with the volume of blood loss. There were noted an increase level of the thymol tests in 2 cases (15.4%). In the second group of patients the following changes in biochemical analyzes were observed: hy-poproteinemia in 2 (2.3%) patients, increase in ALT 1.1-1.9 times higher than normal in 22 patients (24.7%) and AST in 1.1-1.5 times higher than normal in 19 patients (21.3%), an increase in thymol test from 5 to 8 U in 5 people (5.6%), hypoproteinemia (total protein 59 g / l) in 1 patient, in 44 of patients (49.4%) had moderate bilirubinemia from 24.1 to 32.3 ^mol / l, mainly due to the indirect fraction.
In the control group, we practically did not observe such changes in the biochemical and coagulological parameters. Only one patient from this group had an increase in AST to 1.3 ^mol / L.
Dynamic studies of patients in the period of active bleeding (with intensive transfusion therapy), the period with hematomas resorption and hemarthrosis, and without hemor-rhagic complications, regardless of infection with hepatitis B, showed that in patients receiving plasma transfusions 2-4 times, and erythrocytes in 4-5 times the level of transaminases increased. With extensive hematomas (intermuscular, retroperitoneal), gastrointestinal bleeding, and after multiple blood transfusions, the level of bilirubin rose from 1.2 to 6 times the norm, mainly due to the indirect fraction, which may be due to moderate hemolysis of transfused erythrocytes. Therefore, to assess the damage to liver function associated with a viral infection, we took the indicators of tests taken during routine examinations and in the period after stopping bleeding and resorption of hematomas, when blood products were no longer used.
All of the 13 HBsAg-positive patients (group 1) had the following echopathomognomonic signs of chronic hepatitis with different degrees of severity in the ultrasound examination: fibrosclerosis of the liver parenchyma — a heterogeneous structure along the venous ligament along the portal tract and periportal, coarse layers of fibrosis formation, precirototic sealing of the border part of the parenchyma with the stroma of the gallbladder bed; The structure is erased right up to the irregularity along the periphery of the parenchyma. From the angioarchitectonics of the liver — deformation, compaction, thickening of the walls of portal veins and their branches to segmental with their different directions, widening of veins due to portal hypertension. Echogenicity is below average due to the prevalence of dystrophy. An increase in liver size was noted in 8 (61.5%) patients. Moderate enlargement in spleen in 3 (23%) cases. One patient showed signs of liver cirrhosis with severe portal hypertension.
In the second group, 31 of 89 patients (34.8%) had the above signs of chronic hepatitis ofvarying severity, there were no cases of cirrhosis. In patients from the control group, such changes were not detected.
Discussion. According to the results of this study, it was revealed that hepatitis B infection in patients with hemophilia is 87.3%. But not always the presence of serological markers of the virus is accompanied by changes in biochemical tests and ultrasound picture of the liver, which can be treated as a virus carrige (in HBsAg positive patients) or the presence of a trace antibody response to previously existing infection (in HBcAg and / or anti-HBs positive patients). According to the literature [1] antibodies to HBcAg are formed 1-2 weeks
after the detection of HBsAg and persist for life in all who have been infected with hepatitis B, and the combination of HBcAg and anti-HBsAg, with a negative result of HBsAg (as in patients from the 2nd group of ours research), speaks about earlier transferred or carried infection and convalescence. Isolated detection of anti-HBsAg in patients indicates a history of acute hepatitis with convalescence or the presence of postvaccination antibodies. In our study, there were no such cases, which is obviously due to the fact that routine vaccination against hepatitis B in patients with hemophilia in Uzbekistan is not carried out.
According to various authors, clinically expressed forms of liver pathology develop up to 10-15% of patients with hemophilia infected with hepatitis B virus [2,3], which coincides with the our dates.
Viral infection is the most significant, but not the only factor affecting the functional state of the liver in patients with hemophilia. Multiple transfusions of plasma, erythrocytes, cryoprecipitate from various donors leads to sensitization and autoimmune disorders [4,6]. Post hemorrhagic anemia, unavoidable with frequently repeated bleeding in patients with hemophilia, leads to prolonged hypoxia of tissues, including
hepatocytes. In addition, some of the drugs that are often used for various complications in these patients are hepatotoxic (analgesics, sedatives, antibiotics) [2,3]. Nevertheless, with the same effect on the liver of the above non-infectious factors in all the examined groups, according to our studies in the control group, we did not observe pathological changes in the tests characterizing the functional state of the hepatocytes. While in the 1st and 2nd groups of infected patients, such changes took place. Thus, the negative effect of viral hepatitis B on the functional state of the liver in patients with hemophilia is obvious.
Conclusions:
1. The obtained data testify to the high risk of hepatitis B infection rate in hemophilia patients with of development of clinical and laboratory and ultrasound signs of chronic hepatitis and liver cirrhosis.
2. In the group of patients with seronegative for all markers of the hepatitis B virus, there were no laboratory signs of impaired functional status of the liver to the extent that in the groups infected with this virus.
3. There is a direct correlation between infection with the hepatitis B virus and the duration of transfusion therapy.
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