Hepatitis G

Viral hepatitis G is a viral infection with a parenteral transmission mechanism, occurring in an asymptomatic form.

ICD-10 code

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Epidemiology of Hepatitis G

Epidemiological data and clinical observations show that viral hepatitis G is an infection with a parenteral mechanism of pathogen transmission. It has now been established that HGV RNA is often detected in individuals who have undergone blood transfusions and parenteral interventions (detected in 20.8% of those examined). HGV RNA is rarely detected in volunteer donors (1.3%), and much more often in those who regularly donate blood (12.9%). In this case, the pathogen is transmitted through blood or its products. When testing commercial plasma for the preparation of blood products, collected in different countries, HGV RNA was detected in 7-40% of plasma samples.

HGV is widespread without significant age or gender differences: in Germany - 2-4.7% of the population, in Russia - 3.3-8, in France - 2-4.2, in Italy - 1.5, in Spain - 3, in the Netherlands - 0.1-1.5, in Japan - 0.9, in Israel - 5, in South Africa - 20, in the USA - 1.5-2%.

The virus is transmitted exclusively parenterally. Detectability of HGV RNA is associated with blood transfusions and a rich parenteral history. In intravenous drug addicts, the virus is detected in 24% of cases. In patients receiving hemodialysis, the frequency of virus detection ranges from 3.2 to 20%. In volunteer blood donors in the United States, the proportion of HGV infection is from 1 to 2%, which is considered a very high figure. For example, the detection of HBV and HCV in the US population is significantly lower. According to domestic researchers, the hepatitis G virus is detected in blood donors with a frequency of 3.2-4%, in hemodialysis patients - in 28, in somatic patients - in 16.7, in patients with HCV infection - in 24.2, in patients with hemophilia - in 28% of cases.

There is evidence of the existence of sexual and vertical transmission routes of infection. According to C. Trepo et al. (1997), the frequency of HG viremia in France among those suffering from sexually transmitted diseases (syphilis, HIV infection, chlamydia) is 20, 19 and 12%, respectively, which turned out to be higher than in the population as a whole. K. Stark et al (1996) cite data that the frequency of detection of HGV RNA in homosexuals and bisexuals who do not take drugs in Germany is 11%, which is higher than in the population as a whole; at the same time, the frequency of detection of HGV RNA was higher in people with a larger number of sexual partners. The existence of a vertical transmission route of HGV is currently under study. Literature data show that in children born to HGV-positive mothers, HGV RNA is detected in 33.3-56% of cases, and transmission of the virus does not depend on the HGV RNA titer in the mother's blood serum. At the same time, children born as a result of operative delivery (cesarean section) were HGV RNA-negative, and some of the children born naturally, HGV RNA-negative in the first days and weeks of life, became HGV RNA-positive later. In addition, HGV was not detected in the umbilical cord blood. All this indicates a higher probability of intranatal and postnatal infection.

A study was undertaken of blood plasma and serum from patients with various liver diseases (acute and chronic hepatitis, autoimmune hepatitis, primary biliary cirrhosis, hepatocellular carcinoma, etc.) from different parts of the world.

Almost all liver diseases were associated with cases of HG viremia. HGV RNA was detected most frequently in patients with CHC (in 18 of 96 patients from Europe); less frequently in patients with chronic hepatitis "neither A, nor B, nor C"

(in 6 of 48 patients from South America, in 9 of 110 from Europe), as well as in patients with autoimmune (in 5 of 53 patients from Europe) and alcoholic hepatitis (5 of 49 patients from Europe).

According to Russian clinicians, HGV RNA is detected in the blood serum of patients with chronic liver diseases with a very high frequency (26.8% of cases).

Among patients with CHB, individuals with simultaneous HGV viremia were identified, but such a combination was significantly less common than combined chronic HCV infection and HGV infection.

Of great interest after the discovery of НСV are the results of testing for НСV RNA in risk groups for parenteral infection, as well as in volunteer donors.

Frequency of HG viremia in patients at high risk of parenteral infection and in volunteer donors (linnen J. et al., 1996)

The contingent of those examined	Region	Number of subjects surveyed	HGV detection rate
			Total HGV	Only HGV	HGV+ HBV	HGV+ HCV	HBV + HCV
Patient groups at high risk of parenteral infection
Hemophiliacs	Europe	49	9	0	0	8	1
Patients with anemia	Europe	100	18	11	1	6	0
Drug addicts	Europe	60	20	6	1	11	2
Volunteer donors
Blood donors	USA	779	13	13	0	0	0
Donors excluded from fresh blood donation (ALT>45 VI U/ml)	USA	214	5	4	0	0	1
Donors excluded from donating blood for freezing (ALT >45 IU/ml)	USA	495	6	4	0	1	1

As follows from the presented data, HG viremia is detected with approximately the same frequency in hemophiliacs (9 out of 49) and patients with anemia (18 out of 100) receiving multiple blood transfusions.

Among drug addicts, every third one has HGV infection. Moreover, in all risk groups there are a considerable number of patients with mixed infection caused by two, and sometimes even three, hepatotropic viruses. The most common combination is in the form of НСV and HGV infection.

The results of the donor blood screening are interesting. Volunteer donors could be divided into two categories. The first category included donors considered healthy, and their blood was used for transfusions. The second category included other donors whose serum showed increased ALT activity (more than 45 U/l), and therefore they were excluded from donating blood.

As a result of testing, it was revealed that among 779 first-category donors, 13 (1.7%) had blood serum positive for HGV RNA.

At the same time, among donors of the second category (709 people), with approximately the same frequency - 1.5% of cases (11 people), sera with the presence of HGV RNA were detected.

Consequently, among donors with both normal and elevated transaminase activity in the blood serum, the proportion of people with HG viremia, who are capable of transmitting the hepatitis G virus to recipients during blood transfusion, was the same.

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Causes of Hepatitis G

Hepatitis G virus (HGV GBV-C) belongs to the flavivirus family. It was discovered in 1995 in the blood of a surgeon who had acute viral hepatitis of unknown etiology. Its genome consists of single-stranded RNA: structural genes are located at one end (region 5), and non-structural genes are located at the other (region 3). The length of HGV RNA varies from 9103 to 9392 nucleotides. Unlike HCV RNA, HGV lacks a hypervariable region responsible for the diversity of genotypes. There may be three genotypes and several subtypes of the virus.

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Pathogenesis of hepatitis G

Pathobiological features of HGV persistence in humans have not yet been studied, which is due to its recent identification, low incidence of viral hepatitis G and frequent coinfection with viral hepatitis B, viral hepatitis C and viral hepatitis D. The site of viral replication in the body has not yet been established, although HGV RNA has been detected in peripheral blood lymphocytes, including in its absence at this time in the serum. In recent years, it has been shown that in patients with HIV infection, the disappearance of HGV during interferon therapy for chronic hepatitis C leads to a decrease in life expectancy and earlier death at the AIDS stage. An analysis of the mortality of HIV-infected patients at this stage of the disease reliably showed a higher mortality among patients who did not have the HGV virus and, especially, among those who lost this virus during the observation period. It is believed that the G virus blocks access of the HIV pathogen to the cell. The putative substrate (CCR5 protein) and mechanism of blocking have not been established.

An important aspect of the problem is the evidence of the ability of HGV to cause acute hepatitis and induce chronic hepatitis. Taking into account the detection of this agent in patients with acute and chronic liver damage with seronegativity for other hepatitis viruses, it can be assumed that the hepatitis G virus has such an ability. However, there is no clear evidence yet, and the available indirect data are contradictory.

It is known that, when entering the body parenterally, the virus circulates in the blood. HGV RNA begins to be detected in the blood serum 1 week after transfusion of infected blood components. The duration of viremia corresponds to the maximum observation period - 16 years. More than 9-year examinations of patients with persistent HGV infection have shown that both high (up to 107/ppm) and low (up to 102/ml) RNA titers are observed, while the titers can remain constant during the study period or their wide fluctuations (up to six orders of magnitude) are noted, as well as the periodic disappearance of HGV RNA in serum samples.

HGV RNA was detected in liver tissue (Kobayashi M. et al., 1998). However, it turned out that not every case of confirmed HG viremia had HGV RNA detected in the liver. However, there is very little information in the literature on this extremely important issue. In vitro studies have shown that the virus is grafted onto hepatocyte and hepatoma cell cultures and does not replicate on lymphoma cell cultures. Experimental infection of primates with HGV does not cause liver damage in chimpanzees, whereas intralobular necrotic-inflammatory changes and inflammatory infiltration of the affected tracts were detected in marmosets.

From the HG virus cultured on CHO cells, the E2 protein was isolated and partially purified, on the basis of which an ELISA test was prepared for the detection of antibodies to HGV-anti-E2 in the blood serum. Studies have shown that anti-E2 appear in the blood serum of patients after the disappearance of HGV RNA from their blood serum and recovery from hepatitis of this etiology.

Antibodies to hepatitis G virus are antibodies to the surface glycoprotein E2 of HGV class IgG and are currently designated as anti-E2 HGV. They can be detected in the blood for a relatively short time simultaneously with HCV RNA, but then RNA HGV disappears, and only anti-E2 HGV are identified in the blood serum. Therefore, anti-E2 HGV serves as a marker of the body's recovery from the hepatitis G virus.

Symptoms of Hepatitis G

To date, cases of acute viral hepatitis C have been described. The disease occurs both with increased aminotransferase activity and subsequent detection of HGV RNA in the blood serum of patients, and in an asymptomatic form. Probably, this pathology can also occur in the form of fulminant hepatitis, since approximately half of the cases of this nosology cannot be attributed to either viral hepatitis A or viral hepatitis E. However, the role of the hepatitis G virus in the development of the fulminant form of infection is controversial and has not been precisely established.

Acute hepatitis G may be prone to becoming chronic. The frequency of detection of HGV RNA among patients with cryptogenic chronic viral hepatitis is 2-9%. In West Africa, these figures are even higher. It should be noted that this pathogen is most often coinfected with viruses B, C and D, especially in patients at risk (parenteral, sexual transmission). Its presence in patients with other chronic hepatitis does not affect the symptoms and severity of the course, the outcome of the disease, including the results of antiviral therapy.

Despite the above data, the role of HGV in the development of clinically significant and pronounced forms of hepatitis is still disputed and questioned. Normal ALT activity and the absence of other signs of hepatitis in people infected with the virus once again prove this. The high frequency of HGV detection in patients with hepatocellular carcinoma is apparently associated with the frequency of HCV coinfection.

Taking into account the results of epidemiological studies, although still limited, it can be stated that the detection of HGV infection is combined with a wide range of liver lesions: from acute cyclic hepatitis and chronic forms to asymptomatic carriage.

Research by H. Alter et al. (1997) found that approximately 15% of HGV-infected blood recipients do not have clinical and biochemical signs of hepatitis.

According to the same researchers, in some established cases of hepatitis, when only HGV was identified in the blood serum and other known hepatotropic viruses were not detected, the increase in ALT activity was insignificant, and there was practically no relationship between the level of detectable HGV RNA and ALT values.

However, other studies (Kobavashi M, et al., 1998, Kleitmian S., 2002) show a clear relationship between the detection of HGV RNA and the clinical and biochemical manifestations of acute hepatitis.

The literature provides isolated descriptions of cases of acute hepatitis G. Thus, in the publication of J. Lumen et al. (1996) a graphic example of the post-transfusion development of hepatitis G is given in a patient who underwent surgery with a blood transfusion.

Four weeks after the operation, the patient showed an increase in ALT activity, reaching a peak of 170 U/ml (normal 45 U/ml) 12 weeks after the operation. After 1 month, transaminase activity returned to normal and remained the same during the next 17 months of observation and beyond. Results of serological studies for hepatitis A, B viruses.

C were negative, while at the time of the increase in ALT activity and then against the background of its normalization, HGV RNA was detected in the patient's blood serum by the PCR method. Negative results for HGV were recorded with persistently normal ALT activity indicators between the 62nd and 84th weeks of observation (11 months after the decrease in ALT activity).

A retrospective study of donor serum transfused to this patient showed the presence of HGV RNA.

When screening blood sera from 38 patients with sporadic non-A, non-E hepatitis from 4 US states (for the period 1985-1993), HGV RNA was detected in 5 (13%), and in 107 patients with acute hepatitis C - in 19 (18%). Comparison of the clinical picture of hepatitis G as a monoinfection with the picture of coinfection caused by hepatitis C and G viruses showed no differences between them (Alter M. and et al., 1997). Other studies have also shown no significant effect of HG virus infection on the course of viral hepatitis A, B and C when combined.

At the same time, the hepatitis G virus is significantly more often detected in the blood of patients with hepatitis B or C (acute and chronic). Thus, HGV-positive were 1 out of 39 (2.6%) patients with acute hepatitis B, 4 out of 80 (5%) patients with chronic hepatitis B, 5 out of 57 (18.8%) patients with chronic hepatitis C and 1 out of 6 children with chronic hepatitis B+-C.

Diagnosis of Hepatitis G

Acute or chronic viral hepatitis C is diagnosed after other etiologic causes of hepatitis have been excluded. HGV is currently detected by reverse transcription PCR amplification. Two companies, Boehring Mannheim Gmbh and ABBOTT, produce test systems for detecting HGV RNA, but they are recommended for scientific research only. Many laboratories, including those in Russia, use their own systems. They can detect discrepancies in the results of blood serum tests for HGV RNA. An enzyme immunoassay has been developed that can detect the presence of anti-HGV class IgG to the E2 protein in serum, which may be the main target for the humoral response. Attempts to create a test system for detecting anti-E2 class IgM have so far been unsuccessful. Studies have shown that anti-E2 is detected if HGV RNA is absent from the blood serum. A low frequency of anti-E2 detection has been established in blood donors (3-8%), much higher in plasma donors (34%). and the highest frequency is noted in drug addicts (85.2%). The data provided indicate a high frequency of spontaneous recovery from this infection.

Specific diagnostics of HG virus infection is based on detection of HGV RNA in blood serum using PCR. The primers used for PCR are specific to the 5NCR, NS3 nNS5a regions of the viral genome as the most conservative. Primers for PCR on HGV are produced by Abbott (USA) and Boerhmger Mannheim (Germany). Among domestic companies, Amplisens (Center for Epidemiology) and a number of others produce primers for PCR on HGV.

Another method for diagnosing HGV infection is a test to detect antibodies to the surface glycoprotein E2 of HGV. Based on ELISA, test systems have been created to detect anti-E2 HGV, for example, the test system from Abbott (USA).

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Differential diagnostics

Since there is no convincing data on the possible role of HGV in the development of clinically significant forms of hepatitis in humans, questions of differential diagnosis remain open, and the diagnostic value of detecting HGV RNA is still unclear.

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Treatment of Hepatitis G

When the acute phase of viral hepatitis C is detected, the same treatment measures should be taken as for acute HBV and HCV infections. In patients with chronic hepatitis B and chronic hepatitis C, simultaneously infected with HGV, during interferon therapy, sensitivity of the pathogen to this drug and to ribavirin was detected. By the end of the course of treatment, 17-20% of those treated with interferon did not detect HGV RNA in the blood. A positive response was associated with a low level of RNA in the blood serum before the start of therapy. Despite the data obtained, a treatment regimen for chronic viral hepatitis C has not been developed.