Chronic hepatitis C: causes

The cause of chronic hepatitis C - the hepatitis C virus (HCV) is a small virus, 30-38 nm in size, has a shell and an internal part - the core. The shell contains glycoproteins E1 and E2, NS1. The internal part contains the virus genome - a long single-stranded linear RNA and the C-antigen protein (C-core protein).

The virus genome has regions encoding the synthesis of structural and non-structural proteins. Structural proteins include the C-protein of the core and the E1, E2 membrane glycoproteins. Non-structural proteins include enzymes that play a role in virus replication, RNA-dependent RNA polymerase, NS2, NS4 proteins, NS3 helicase (metalloproteinase). The key role in the replication of the C virus belongs to NS3 proteinase - an enzyme that catalyzes the final stage of the synthesis of the viral polyprotein. Antibodies circulating in the blood are produced for each of the structural and non-structural proteins. These antibodies do not have virus-neutralizing properties.

There are 6 genotypes of the hepatitis C virus, the classification of which is based on the analysis of the 5'-terminal region of the non-structural region NS5 (genotypes la, lb, 1c, 2a, 2b, 2c, 3a, 3b, 4, 5, 6).

In North Africa, 4 genotypes are common, in North and Southeast Asia and the Far East - 1, 2, 6, in the USA - 1.

There are over 500,000,000 hepatitis C virus carriers worldwide. Genotype 1b is associated with a more severe course of the disease, higher serum HCV RNA levels, a worse response to antiviral therapy, and a higher likelihood of serious hepatitis C relapse after liver transplantation. Genotype 4 is associated with a poor response to interferon therapy.

Chronic HCV infection usually begins in a mild form, but in 50% of patients the disease progresses over 10 years, in 10-20% - liver cirrhosis develops, less often - liver cancer.

Hepatitis C virus is an RNA virus. Serum markers of hepatitis C virus are RNA of the virus and antibodies to HCV (HCVAb).

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How is hepatitis C transmitted?

Chronic hepatitis C is transmitted in several ways:

• parenteral, especially transfusion (blood transfusion, its components - cryoprecipitate, fibrinogen, factors VIII and IX; parenteral administration of various drugs; hemodialysis); HCV is the main cause of post-transfusion hepatitis (85-95% of all cases);
• sexual tract;
• from mother to fetus (via the placenta).

Histological manifestations of chronic hepatitis C vary from CPH to CAH with or without cirrhosis. The spread of hepatitis C depends largely on environmental factors.

There are 2 main mechanisms of liver damage by the hepatitis C virus:

• direct cytopathic (cytotoxic) effect of the virus on hepatocytes;
• immune-mediated liver damage, which is supported by data that viral hepatitis C can be associated with autoimmune diseases (Sjogren's syndrome, cryoglobulinemia, etc.), as well as the detection of lymphoid cell infiltration consisting of B- and T-lymphocytes in liver biopsies of patients with viral hepatitis C.

Markers of the hepatitis C virus are detected among medical personnel of hematology departments in 12.8%, in patients with blood diseases - in 22.6%, in patients with chronic hepatitis - in 31.8%, in patients with liver cirrhosis - in 35.1% of cases, among the population of Russia - in 1.5-5% of residents.

Immunity in hepatitis C is not optimal (it is called suboptimal), which does not provide reliable control over the infectious process. Therefore, acute viral hepatitis C so often transforms into chronic, and this also explains the frequent reinfection with the C virus. The hepatitis C virus "slips" from immunological surveillance. This is explained by the unique ability of the hepatitis C virus to constantly change the antigen structure, to renew itself many times within even one minute. Such constant variability of the hepatitis C virus leads to the fact that within 24 hours 10 ^10-11 antigen variants of HCV appear, which are close, but still immunologically different. In such a situation, the immune system does not have time to continuously recognize more and more new antigens and continuously produce antibodies that neutralize them. In the HCV structure, maximum variability is noted in the membrane antigens, the protein C of the core changes little.

The course of HCV infection extends over many years (like a slow viral infection). Clinically expressed chronic hepatitis develops on average after 14 years, liver cirrhosis - after 18, hepatocarcinoma - after 23-18 years.

A distinctive feature of acute viral hepatitis C is a torpid, latent or low-symptom course, usually remaining unrecognized for a long time, at the same time gradually progressing and subsequently quickly leading to the development of liver cirrhosis with hepatocellular carcinoma (hepatitis C virus is a “silent killer”).

Markers of the replication phase of the hepatitis C virus are the detection of anti-HCVcoreIgM and IgG in the blood with the anti-HCVlgG/IgM coefficient within 3-4 U in the absence of aHTH-HCVNS4 and the detection of HCV-RNA in the blood.

The hepatitis C virus can also replicate extrahepatically, including in monocytes.

Mechanisms of liver damage in chronic hepatitis C

The virus is thought to have a direct cytopathic effect. This effect is distinct from the damage caused by HBV, which is thought to be immune-mediated. There is growing evidence that immune mechanisms also play a role in the chronicity of HCV infection.

Cytotoxic flaviviruses tend to cause direct hepatocellular injury without significant inflammation. In chronic HCV infection, liver histology reveals minimal damage despite progression. Lymphocytic response is weak, with hepatocyte cytoplasmic eosinophilia. Unlike chronic hepatitis B, treatment of chronic HCV infection with IFN is accompanied by a rapid decrease in ALT activity and HCV-RNA concentration.

There is a correlation between the severity of the disease and the level of viremia. Very high levels of viremia and severe liver damage are observed in patients with chronic HCV infection after liver transplantation.

The immune response to HCV is weak, as evidenced by the increased activity of ALT, which is accompanied by an increase in HCV-RNA titers. With inoculation of a significant number of viral particles (blood transfusion), liver disease is more severe than with a less massive entry of viruses into the body (intravenous drug use).

HCVcarriers have persistent HCV viremia without clinically evident liver disease. There is no correlation between HCV RNA levels in liver tissue and histologic activity.

Immunosuppressant therapy reduces the activity of serum transaminases, although viremia increases.

Immunoelectron microscopy results suggest that intralobular cytotoxic T cells support liver injury. Cytotoxic lymphocytes recognize epitopes of the HCV core and protein coat. In vitro autologous hepatocytotoxicity studies have convincingly demonstrated that HLA 1-restrictive CD8 ⁺ T cell toxicity is an important pathogenetic mechanism in chronic HCV infection.

Serological tests for autoantibodies (antinuclear, smooth muscle, and rheumatoid factor) are positive. However, these autoantibodies do not affect the severity of the disease and have no pathogenetic significance.

Evidence of liver cytotoxicity has been obtained in chronic HCV infection. The immune response to HCV is also clearly documented, but its role as a protective factor and as a factor causing chronic infection remains unclear.