TTV infection

The name "transfusion transmitted virus" - a virus transmitted by transfusion (TTV) indicates its initial detection in patients with post-transfusion hepatitis. TTV belongs to the Circoviridae family. The virion is a particle without an envelope, 30-50 nm in size, consisting of a single-stranded DNA of a ring-shaped structure containing 3852 nucleotides. The presence of hypervariable and conservative regions of viral DNA has been established.

Analysis of nucleotide sequences of TTV isolates obtained in different regions of the world has revealed genotypes (up to 16) and several subtypes of this virus. No relationship has been found between the circulation of a specific TTV genotype and a specific territory. The most common genotypes are Gla and Gib. Several TTV genotypes may be detected in the same patient, which is associated either with multiple infections with this virus or with mutations occurring in the viral DNA.

Epidemiology of TTV infection

TTV is widespread but unevenly distributed. Its prevalence among the population of European countries is 1.9-16.7%, in Asian countries - 11-42%. In the USA and Australia, the detection rate is 1-10.7% and 1.2%, respectively. TTV is most often detected among the population of African countries (in 44-83% of those examined). The detection rate of TTV increases with the age of those examined and, especially, among certain groups of the population. Thus, the percentage of TTV DNA detection in the blood of donors is significantly higher than in the population (Scotland - 46%, Finland - 73%, Singapore - 98%). The group with an increased risk of TTV infection includes drug addicts, prostitutes, homosexuals; patients with hemophilia and patients on chronic hemodialysis, i.e. people with an increased risk of infection with hepatitis viruses with parenteral and sexual transmission of the pathogen.

Although TTV was first detected in patients with parenteral hepatitis, further studies showed that TTV can also be transmitted via the fecal-oral route. The virus was proven to be present in bile, feces, and simultaneously in blood serum. TTV was detected in the blood of some agricultural (bulls, pigs, chickens, sheep) and domestic animals (dogs, cats). Testing of animal milk for TTV DNA gave positive results. Finally, an outbreak of acute hepatitis with the fecal-oral transmission mechanism was registered in China, in the occurrence of which the role of known hepatotropic viruses was excluded. At the same time, it was detected in the blood of all 16 patients tested for TTV DNA, which allowed us to assume the etiologic role of TTV in the occurrence of this outbreak.

The data obtained indicate multiple mechanisms of transmission of TTV. Information on susceptibility to TTV is not available.

As established by T. Nishizawa et al. (1997) and H. Okamoto et al. (2000), TTU is detected with high frequency in patients with chronic hepatitis “neither A nor G” (46%), in patients with hemophilia (68%), in drug addicts (40%), in patients on hemodialysis (46%), and also in blood donors (12%).

Detection of TTV DNA in the blood serum of various Japanese populations (Okamoto H. et al., 1998)

Group	Number of surveyed	Frequency of TT DNA detection
Fulminant hepatitis "non-A, non-G"	19	9 (47%)
Chronic liver disease "non-A, non-G"	90	41 (46%)
Chronic hepatitis	32	15(48%)
Cirrhosis	40	19 (48%)
Hepatocellular carcinoma	18	7 (39%)
Hemophilia	28	19 (68%)
Drug addicts who use drugs intravenously	35	14 (40%)
Patients on hemodialysis	57	26 (46%)
Blood donors	290	34 (12%)

The high frequency of TTV detection (47%) in patients with fulminant hepatitis, with chronic liver diseases of unknown etiology and its relatively low detection in blood donors (12%) are notable. This fact may indicate the hepatotropism of TTV. In addition, there is indirect evidence of possible hepatotropism of TTV: in patients with post-transfusion hepatitis, TTV DNA was detected in the blood serum and liver in the same concentration, and sometimes the concentration of TTV DNA was higher in the liver (Okamoto H. et al., 1998),

The discovery of TTV by Japanese scientists served as the basis for a series of studies in other countries. The main interest was to what extent this virus is involved in liver damage in other regions of the world.

Doctors from the London Institute of Hepatology (Naumov N. et al, 1998) found TTV DNA in 18 of 72 patients (25%) with chronic liver disease and in 3 of 30 healthy individuals (10%). In most patients with chronic liver disease and the presence of TTV DNA in the blood serum, no significant biochemical changes or histological signs of significant liver damage were detected. Genotyping of 9 isolates showed the presence of the same genotypes as in Japan: 3 patients were infected with genotype 1, which had 4% nucleotide sequence variability, and 6 had genotype 2 with 15-27% nucleotide divergence.

Scientists from the University of Edinburgh (Simmonds P. et al., 1998) detected TT viremia in only 19 (1.9%) of 1000 voluntary regular blood donors, and TTV infection was observed only in elderly donors (average age - 53 years). Contamination of blood coagulation factor concentrates with this virus was high - 56% (10 of 18 samples). TTV infection was verified in 4 (19%) of 21 patients with fulminant liver failure of unknown etiology. Moreover, in 3 of 4 cases TTV was detected at the onset of the disease, and, therefore, its etiologic role in the development of severe hepatitis cannot be excluded.

According to American researchers (Charlton M. et al., 1998), TTV infection was detected in 1% of cases in blood donors (1 out of 100), 15 (5 out of 33) in patients with cryptogenic liver cirrhosis, 27 (3 out of 11) in patients with idiopathic fulminant hepatitis, 18 (2 out of 11) in patients who received blood transfusions, and 4% (1 out of 25) in patients without a history of parenteral manipulations. Thus, a history of blood transfusions is associated with a high risk of TTV infection (relative risk 4.5).

It has been proven that TTV can be transmitted not only parenterally, but also by the feco-oral route (Okamoto H. et al, 1998), as well as by airborne droplets and sexually (Yzebe D, et al., 2002).

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Pathogenesis of TTV infection

Experimental infection of chimpanzees and marmosets resulted in the appearance and subsequent disappearance of TTV DNA in the blood serum of all monkeys and was not accompanied by an increase in ALT and AST activity or morphological changes characteristic of acute hepatitis.

Cases of TTV DNA appearance, persistence and subsequent disappearance in patients have been documented. In patients with post-transfusion hepatitis neither A nor G, the rise and fall of TT virus titers were associated with an increase and decrease in ALT and AST activity. With normalization of aminotransferase activity, TT virus was not detected. Indirect confirmation of the hepatotropism of this virus is the fact that TT virus is detected in liver tissue in concentrations exceeding those in blood serum by 10-100 times. At the same time, long-term persistence of TTV DNA (for 22 years) without biochemical and morphological changes in the functions and structure of the liver was revealed. The possibility of TTV DNA integration into the hepatocyte genome is currently rejected. At the same time, there is no explanation for the mechanism that ensures long-term preservation of the virus in the human body.

Symptoms of TTV infection

The high frequency of TTV detection in patients with fulminant hepatitis and liver cirrhosis of unspecified etiology (cryptogenic) initially suggested the role of this virus in the development of acute viral hepatitis with a severe course and frequent outcome in liver cirrhosis. However, numerous subsequent studies have not revealed any clinical features of the course of hepatitis depending on the detection of TTV, therefore the etiological role of TT virus in the development of acute or chronic hepatitis, cirrhosis and primary hepatoma requires further study.

There are isolated descriptions of symptoms of acute, mainly post-transfusion hepatitis TTV in adult patients. The incubation period varies from 6 to 12 weeks. The disease begins with an increase in body temperature, mainly within 38 C, the appearance of asthenodyspeptic syndrome, an increase in the size of the liver and hyperenzymemia - an increase in the activity of ALT, AST, GGT, etc. (Kanda T., 1999). In most cases, acute hepatitis TTV occurs in anicteric form.

Coinfection of TTV hepatitis with other viral hepatitis is observed much more often than TT viral monoinfection (Hayaski K. et al., 2000).

There are no publications in the available literature regarding TTV infection in children.

Diagnosis of TTV infection

Diagnosis of TTV infection is based on detection of TTV DNA in the blood serum (liver) using PCR. The significance of antibodies to TTV has not been established.

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How is TTV infection prevented?

TTV infection is prevented in the same way as other viral hepatitis.