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UDC 616.36-002-004:616.151.514-07(571.15) doi.org:10.31684/2541-8475.2019.1(13).57-61
PARENTERAL VIRAL HEPATITIS IN PEOPLE WITH HEMOPHILIA: WAYS TO SOLVE THE PROBLEM
1Altai State Medical University, Barnaul 2Peoples' Friendship University of Russia, Moscow
M.A. Nikonorova1, N.V. Karbysheva1, G.M. Kozhevnikova2, A.N. Mamaev1, V.V. Shevchenko1, O.V. Beskhlebova1
Clinical and laboratory examination of 80 patients with hemophilia aged 16-59 living in the Altai Krai was carried out. From childhood, all patients have repeatedly received cryoprecipitate or fresh frozen plasma. In 50 of 80 patients with hemophilia (62.5%), chronic viral hepatitis (CVH) was diagnosed: CVH B and C in 1 patient (2%), CVH B in 2 (4%) and CVH C in 47 patients (94%). The mean age of patients with hemophilia and CVH is 38.4 (22-59 years). All patients have no data on the prior acute hepatitis B or C. In 30%, we noted an increase of ALT (in 30%), AST (in 20.4%), GGT (in 26.6%), ALP (in 13.3%). The obtained biochemical data indicate the presence of a minimal degree of activity of chronic hepatitis. Key words: hemophilia, hepatitis C, hepatitis B, liver cirrhosis.
Parenteral viral hepatitis B and C are one of the most urgent problems of both global and domestic health care. These infections are associated with lethal outcomes in patients with acute hepatitis, as well as with the cases of development of chronic liver diseases including cirrhosis and primary liver cancer [1, 2]. According to the World Health Organization (WHO), around 50 million people are infected with hepatitis B annually, and up to 2 million people die. From 100 to 200 million people are carriers of hepatitis C virus. According to WHO forecasts, in the next 10-20 years, a number of patients with liver cirrhosis can increase by 60%, patients with cancer by 68%, and the mortality from liver diseases can increase twice [3]. In 2015 alone, 1,34 million people died of viral hepatitis, which may be compared to deaths from tuberculosis and HIV infection. Most of deaths from viral hepatitis in 2015 were related to chronic liver diseases (720,000 deaths due to complications of liver cirrhosis) and primary liver cancer (470,000 deaths due to hepa-tocellular carcinoma). Globally, in 2015, about 257 million people lived with chronic HBV infection and 71 million people with chronic HCV infection [2].
It is widely recognized that blood and blood preparations are the most important factors in infection contamination with hepatitis viruses with parental transmission mechanisms. Patients with hemophilia receiving regular treatment with blood preparations belong to the group of increased risk of infection with hepatitis viruses [4].
All known to date antihemophilic drugs filling the deficiency of plasma coagulation factors VIII and XI (FVIII and FXI) in patients with hemophilia can be divided into 3 groups: non-virus inactivated, virus inactivated, and recombinant. In recent years, significant progress has been made in providing patients with hemophilia living in the Russian Federation with virus inactivated and recom-
binant factors, coagulation factor concentrates for "home treatment". However, in urgent situations, in this patients it is possible to use blood preparations that have not passed reliable procedures for virus inactivation. Before 2006, blood preparations were very widely used without quarantine and without viral inactivation procedures, which led to the widespread of viral hepatitis in this groups of patients [5, 6]. Thus, according to many researchers, the rate of detection of hepatitis virus markers remains high to date and reaches 60% in adult patients and 4.7% in children under 18 [7, 8, 9, 10].
Clinical implications of chronic hepatitis in patients with hemophilia are most often absent for many years or expressed in the least, which makes diagnosis difficult and causes the development of sluggish chronic inflammatory process. Regular transfusions of blood components and preparations (fresh frozen plasma, erythrocyte concentrate, coagulation factors concentrates, etc.), as well as toxinemia, the frequency of which significantly increases in the presence of other complications, such as resorption of hematomae, are the starting mechanism of activation of autoimmune processes enhancing cytolytic syndrome. In this regard, morphological signs of liver parenchyma damage may be very deep and often nonreversible. As a rule, these processes in this category of patients occur gradually and asymmetrically; in addition, they can cause the formation of hepatocellular carcinoma [6, 11]. However, despite the ease of the course, the frequency of chronic liver diseases and associated mortality is 17 times higher in patients with hemophilia, and hepatocellular carcinoma is 6 times more frequent than in the population on the whole [12, 13]. Complications of chronic hepatitis G liver cirrhosis (e.g. esophagus variceal hemorrhage, hepatic encephalopathy), and hepatocellu-lar carcinoma are the second most frequent cause of death in patients with hemophilia [14, 15, 16].
Dynamics of progression of chronic liver disease depends on many factors: age, sex, HCV genotype, inflammation activity, mixed infection of hepatitis B virus (HBV) or human immunodeficiency virus (HIV), other infections associated with blood transfusion, presence of metabolic disorders (diabetes, obesity, fatty hepatosis, increased concentration of iron in serum), and smoking [17, 18, 19, 20]; in general, this comorbid pathology affects psychosomatic features and quality of life of these patients [21, 22, 23, 24].
The research objective is to determine the features of the course of viral hepatitis in patients with hemophilia living in Altai Krai and further tactics of patient management.
Materials and methods
Currently, in Altai Krai, 107 patients with hemophilia aged from 16 to 59 (the mean age is 25.9 (16-33)) are on record in the Polyclinic Department of the Regional Clinical Hospital, among them 65% are residents of Altai Krai districts and 35% are residents of Barnaul. 73 patients have hemophilia A (92%), 7 patients have hemophilia B (8%). 4 patients have light hemophilia course, 8 patients are observed with severe hemophilia, and 68 patients are with moderate hemophilia. All patients have repeatedly received cryoprecipitate or fresh frozen plasma.
Clinical and laboratory examination included: medical history, clinical examination, laboratory tests (general blood test, biochemical blood test with determination of total bilirubin and its fractions, aminotransferase activity, etc.), ultrasound diagnostics of the liver, elastometry of the liver, detection of antibodies to HCV by enzyme immu-nodetection method, detection of viral replication with the help of polymerase chain reaction of HCV RNA, genotyping of HCV and determination of viral load of HCV RNA in blood serum.
Results and discussion
In 50 of 80 patients with hemophilia (62.5%), chronic viral hepatitis was diagnosed: chronic viral hepatitis B and C in 1 patient (2%), chronic viral hepatitis B in 2 patients (4%), and chronic viral hepatitis C in 47 patients (94%). The mean age of patients with hemophilia and chronic viral hepatitis is 38.4 (22-59 years).
In the history of all patients with hemophilia, there is no data on past acute hepatitis B or C, which indicates probable infecting in childhood. Such subjective manifestations of a disease as asthenia and manifestations of dyspeptic character were rather rare. In laboratory examination (Table 1) of patients, 30% were noted to have an increase in ALT, 20.4% in AST, 26.6% in GGT activity, 13.3% in alkaline phosphatase (AP).
Table 1
Indicator N=80 % of patients
ALT (0.0-40.0 U/L) 49-92.7 30%
AST (0.0-37.0 U/L) 61.2-129.6 20.4%
Bilirubin (8.55-20.5 ^mol/L) 10.9-16.9 N
Cholesterol (3.24-5.17 mmol/L) 5.91-7.65 6%
Total protein (65.087.0 g/L) 66.2-82.9 N
AP (270 U/L) 286-452 13.3%
GGT (11.0-61.0 U/L) 72.8-91.5 26.6%
The obtained biochemical data indicate the presence of a minimal degree of activity of chronic hepatitis. According to various researchers, clinically expressed forms of liver pathology develop in no more than 10% of patients with hemophilia [25].
Chronic hepatitis C in patients with hemophilia, long-term infected since early childhood, is characterized by the low-symptomatic course, low biochemical activity in the form of a minimal increase in ALT level (1.3 times) in the absence of significant changes in other indicators of impaired liver function, as well as by the predominance of lb genotype of the causative agent (56.9%) and high viral load (58.5%), occurs with less clinical and laboratory manifestations regarding the amount of complaints, the frequency of liver increase, the severity of cytolytic and immunoinflammatory syndromes than in people without hemophilia. With that, clinical and laboratory manifestations of chronic hepatitis C are not related to the severity of hemophilia by the main indicators of hemostasis, while the relative independence of HCV-infection course from the severity of congenital coagulopa-thy confirms the main importance of the impact of infection in early childhood on the severity of the manifestation and the rate of viral hepatitis C progression.
The study is currently in progress. In the examined patients, 1b genotype of hepatitis C virus and the initial stages of fibrosis (0-2) on a scale prevail.
According to the international guidelines (EASL) for the treatment of patients with CHC, it is extremely important to provide antiviral therapy for CHC in all patients with hemophilia regardless of the stage of the disease (severity of fibrosis), duration of infection, hepatitis activity (levels of ALT and AST), level of viremia and virus genotype. The sooner the therapy is carried out and the elimination of the virus from the body is achieved, the faster the complete structural and functional recovery of the liver will occur. Sustained virologic response (SVR) after the course of antiviral therapy reduces the risk of adverse outcome in persons with
hemophilia [27]. The results of double antiviral therapy (interferon + ribavirin, pegasys + ribavirin, 24-48 weeks) showed high effectiveness of AVT in young people with 3a and 2a genotypes and lack of effect in elderly people with 1b genotype [28]. Antiviral therapy with ledipasvir-sofosbuvir direct antiviral drugs for patients with HCV infection genotype 1 or 4 or sofosbuvir-ribavirin for patients with genotype 2 or 3 shows a sustained virologic response in 12 weeks after treatment being 99% (98/99) in patients with infection genotype 1 or 4; 100% (5/5) in patients with cirrhosis with infection genotype 1 who received treatment; 100% (10/10) in patients with genotype 2; and 83% (5/6) in patients with infection genotype 3. High efficiency and good tolerance among patients with hemophilia was noted [29].
EASL recommendations (2015, 2016) noted that the rate of progression of liver disease to the terminal stage in patients with hemophilia is the same as in HCV-positive persons in the general population. In chronic liver diseases, examination of patients with hemophilia is the same as in persons without hemophilia. For patients with hemophilia, transjugular liver biopsy is a safer procedure. Non-invasive methods can be used to monitor the progression of the disease. Hepatic insufficiency in HCV-positive persons is considered to be one of the most common causes of death in patients with hereditary blood coagulation disorders. The tactics of management of patients with CHC and hemophilia are the same as in the population not suffering from hemophilia, except for the impossibility of histological examination of the liver. New DAA drugs can be used in patients with hemophilia for the treatment of CHC [30].
In May 2016, at the meeting "Croit IV", as a result of discussions among experts from 36 European countries, recommendations were summarized concerning hemophilia therapy, which stated that the treatment of hepatitis C should be provided to all people with hemophilia as a matter of priority by direct action antiviral agents [31].
In April 2016, a round table of experts in the field of hemophilia treatment "Achievements and problems in the treatment of hemophilia" was held, at which a resolution was made on the need to implement the following measures: 1) to maintain the system of centralized provision of patients with hereditary coagulopathy by concentrates of coagulation factors, which has proved its effectiveness and rationality; 2) public health bodies are to pay special attention to the treatment of posttransfusion hepatitis with the use of modern antiviral drugs. Taking into account the specifics of the main disease, consider it appropriate to use non-interferon treatment schemes for CHC in patients with hemophilia and other hereditary coagulopathies; 3) to develop financial provision of diagnostics and antiviral therapy of chronic
hepatitis C in patients with hemophilia and other hereditary coagulopathies; 4) to initiate the professional community to develop federal clinical recommendations (treatment protocol) of medical care for patients with hemophilia and other hereditary coagulopathies with chronic hepatitis C, as well a standard of specialized medical assistance to patients with hemophilia and other hereditary coagulopathies with chronic hepatitis C [32].
Conflict of interest. The authors declare that there is no conflict of interest.
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Contacts
Corresponding author: Nikonorova Marina Anatolyevna, Doctor of Medical Sciences, Associate Professor of the Department of Infectious Diseases and Phthisiology, Altai State Medical University, Barnaul.
656038, Barnaul, Lenina Prospekt, 40.
Tel.: (3852) 566888.
E-mail: [email protected]
Author information
Karbysheva Nina Valentinovna, Doctor of Medical Sciences, Professor, Head of the Department of Infectious Diseases and Phthisiology, Altai State Medical University, Barnaul. 656045, Barnaul, Zmeinogorsky Tract, 75.
Tel.: (3852) 268342. E-mail: [email protected]
Kozhevnikova Galina Mikhailovna, Doctor of Medical Sciences, Head of the Department of Infectious Diseases with courses of Epidemiology and Phthisiology, Peoples' Friendship University of Russia, Moscow.
117198, Moscow, ul. Miklikho-Maklaya, 8.
Tel.: (495) 3654753.
E-mail: [email protected]
Mamaev Andrey Nikolaevich, hemostasiologist, Senior Researcher, Altai State Medical University, Barnaul.
656038, Barnaul, Lenina Prospekt, 40. Tel.: (3852) 566888. E-mail: [email protected]
Shevchenko Valery Vladimirovich, Candidate of Medical Sciences, Associate Professor of the Department of Epidemiology, Microbiology and Virology, Altai State Medical University, Barnaul. 656024, Barnaul, ul. Lyapidevskogo, 1, office 710. Tel.: (3852) 689471. E-mail: [email protected]
Beskhlebova Olga Vasilyevna, Candidate of
Medical Sciences, Assistant of the Department of
Infectious Diseases and Phthisiology, Altai State
Medical University, Barnaul.
656045, Barnaul, Zmeinogorsky Tract, 75.
Tel.: (3852) 268342.
E-mail: [email protected]
