Tomasiewicz, Roma Modrzewska, Anna Lyczak, Grazyna Krawczuk,
Department of Infectious Diseases, Medical University of Lublin,
Biernackiego 9, 20-089 Lublin, Poland
Correspondence to: Krzysztof Tomasiewicz, MD, PhD,
Biernackiego 9, 20-089 Lublin, Poland.
TT virus (TTV) was first isolated in 1997 from the patient with
acute post-transfusion hepatitis. This fact led to the conclusion
that the virus was hepatotropic and could be one of the causative
agents of acute hepatitis. Afterwards, however, the virus was found
in other human tissues and serological studies revealed that it was
widespread. Multiple tropisms of TTV and the fact of its high
incidence in general population are considered to indicate no
medical significance of TTV in human pathology. Here we present a
report of two cases of TTV infection in patients who developed
pancreas cancer. The patients were hospitalized at the Department of
Infectious Diseases due to hepatitis of unknown origin. Since
serological and virological markers of common primary and secondary
hepatotropic viruses were negative, TTV-DNA was found in serum and
was believed to be the only causative agent with probable
hepatotropic action. The patients later developed pancreas cancer
and they underwent operation. The relationship is difficult to
confirm, however the cases we present should be treated as a
preliminary report and a comment on the real role of TTV in human
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: TT virus; Hepatitis; Pancreas cancer; Hepatotropic
Tomasiewicz K, Modrzewska R, Lyczak A, Krawczuk G. TT virus
infection and pancreatic cancer: Relationship or accidental
coexistence. World J Gastroenterol
2005; 11(18): 2847-2849
The medical significance of TT virus (TTV) has not been
completely explained. The virus was first isolated in 1997 in a
Japanese patient with acute posttransfusion hepatitis and considered
a transfusion-transmitted and hepatotropic one. The virus was named
TT both due to initials of the first patient with detectable TTV-DNA
in serum and as an abbreviation of the word
The exact taxonomy of this unenveloped circular
DNA virus has not been established. TTV is related to Circoviridae,
although there are some opinions, that it should belong to a new
family called Circinovirida.
The analysis of TTV infected patients with
symptoms, signs and laboratory results characteristic of acute
hepatitis have revealed that TTV is likely to be associated with
human liver pathology. The fact that the virus was frequently found
in the liver tissue of patients with hepatitis supports this thesis.
However, the liver is probably not the only target of the virus. It
was also identified in the bone marrow, lymph nodes, pulmonary
tissue, spleen, kidney, muscles and pancreas. This indicates that
the virus can replicate in these tissues and that the accurate
assessment of the virus tropism is difficult.
The 10-300 times higher virus concentration in
the liver than in the serum is one of the most evident indication of
its hepatotropic nature.
However, TTV-DNA is likely to either integrate with a host genome or
be present in hepatocytes in the episomal form[3-5].
Since the exact significance of TTV in human
pathology has not been fully explained and its biological action
probably involves integration with the human genome, some authors
undertook studies on its possible role in the oncogenesis. Due to
the association of TTV infection with liver diseases most of them
focused on hepatocellular carcinoma.
We present here two case reports of patients
infected with TTV who developed pancreas cancer. Since the
coexistence of pancreatic cancer and TTV infection has not been
reported to date, we found these cases interesting and worth
The patient, a 60-year-old male was admitted to our Department of
Infectious Diseases of Medical University of Lublin due to moderate
abdominal pain localized in the right upper quadrant and elevated
aminotransferase levels. History revealed that he was hospitalized
due to myocardial infarction 5 mo earlier, and therefore he did not
travel abroad and stayed away from ill individuals, and refrained
from the use of alcohol or drugs.
On the basis of epidemiological data and results
of biochemical laboratory tests, infectious hepatitis was suspected.
On admission the bilirubin level was 3.44 mg/dL, AST level - 222 UL
and ALT - 372 UL (the normal level is up to 37 and 40 UL,
respectively). Other routine biochemical serum examinations were
normal. Morphology revealed no pathology.
Both chest X-ray and abdomen ultrasonography were normal.
Serological and virologic markers of common
primary hepatotropic viruses A, B and C, including anti-HAV IgM, HBs
Ag, HBe Ag, anti-HBe, anti-HBc, HBV-DNA, anti-HCV, and HCV-RNA, were
negative. Moreover, negative results of serological tests excluded
Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection. To
find the cause of liver inflammation the test for autoantibodies was
performed and no antinuclear (ANA), antimitochondrial antibodies
(AMA) and anti smooth muscles antibodies (ASMA) were found. Finally
markers of hepatitis G virus (HGV) and TTV infections were tested.
The test for HGV was negative, however, using qualitative test based
on polymerase chain reaction method, TTV-DNA was found in the
patient’s serum. The patient still had abdominal pain, and both
alkaline phosphatase (AP) and gamma glutamyl transpeptydase (GGTP)
increased to the alarming value, 516 UL (normal range 37-111 UL) and
1 223 UL (normal range 11-43 UL), respectively. CT scan was
performed, first without and then using the radiographic contrast (Ultravist).
The examination showed irregular enlargement of the pancreas head up
to 4 cm in diameter, whereas CT density before contrast
administration was 42-50 HU, and after it 80-104 HU. Simultaneously
the widening of the common biliary tract and intrahepatic biliary
tracts was visible. CT examination was done 2 wk after
ultrasonography. The patient was sent to the Surgical Department,
where pancreas cancer was diagnosed and the patient underwent
operation. Unfortunately it was not possible to test TTV presence in
The patient, a 44-year-old female, was admitted to the
Department of Infectious Diseases of Medical University of Lublin
due to dyspeptic symptoms and moderate pain in the right upper
quadrant. The symptoms appeared two weeks before admission.
The history revealed no health problems and surgery or invasive
diagnostic procedures in the past. In our opinion, the most
important fact in the history was that the patient worked as a nurse
in the surgical ward, so she was likely to be at risk of
hepatotropic virus infection. On admission the biochemical
parameters were as follows: bilirubin level -8.4 mg/dL, AST - 322
UL, ALT - 608 UL. An abdomen ultrasonography, performed on
admission, revealed no pathology. Diagnostic procedures involved
serological and virological markers of common primary hepatotropic
viruses A, B and C. Anti-HAV IgM, HBs Ag, HBe Ag, anti-HBe, anti-HBc,
HBV-DNA, anti-HCV, and HCV-RNA were negative. We also excluded EBV
and CMV infections were also excluded.
The tests for autoantibodies were also negative.
Antinuclear (ANA) and antimitochondrial antibodies (AMA) were
absent. The only positive viral test was TTV-DNA, which was found
using qualitative test based on the PCR method.
Although the hepatoprotective treatment had been
introduced, the patient’s condition aggravated. The bilirubin
level reached 20.1 mg/dL whereas aminotransferase activity decreased
(AST-178 and 310 UL). The level of serum cholestasis markers was
continuously increasing (GGTP reached 1 174 UL). To find the cause
of increasing jaundice, we repeated the abdomen ultrasonography. It
showed the presence of widened intrahepatic biliary ducts and the
hyperechogenic area in the lower zone of pancreas head, suggesting
neoplasm. The patient was sent to the Surgical Department. The final
diagnosis of pancreas cancer was based on the histological
examination of the specimen obtained during operation.
The cases of TTV infection and pancreas cancer coexistence presented
here should arouse special interest and provoke discussion about the
question asked in the title of this paper. Is there any relationship
between TTV infection and oncogenesis in the pancreas or is the
coexistence completely accidental? We have not found any reports
concerning that problem.
There are some reports mentioning the problem of correlation between
TTV infection and the development of different neoplasm. Shiramizu et
al. carried out studies on the virus in the etiology of acute
lymphoblastic leukemia (ALL). They performed the analysis of
peripheral blood mononuclear cells and bone marrow cells, as well as
cerebrospinal fluid and concluded that TTV was unlikely to be
associated with ALL.
Because TTV is suspected of being a potentially hepatotropic virus,
Liwen et al. analyzed patients with chronic hepatitis, liver
cirrhosis, and primary liver cancer, comparing the results in these
study groups with a control group of healthy individuals. The
frequency of TTV infection in hepatocellular carcinoma ranged from
8.1% to 100%. The authors suggested that such a great variability
made explicit conclusions concerning the correlation between TTV
infection and both chronic hepatitis and liver cancer impossible.
Similar results were obtained by Japanese[8,9]
and Italian researchers.
Moriyama et al. demonstrated that the virus had no impact on
clinical and serological profile of HBV and HCV infection.
TTV did not change the results of chronic hepatitis B therapy with
lamivudine. These conclusions were supported by the results of
molecular research carried out by Yamamoto et al. They
confirmed that the TTV genome was not integrated into the host
hepatocyte DNA, which is probably necessary to initiate potential
TTV co-infection was not associated with the
presence of B-cell non-Hodgkin lymphoma. Cacoub et al. found
TTV-DNA in only 7% of patients.
On the other hand, according to Garbuglia et al., the
significant prevalence of TTV DNA in lymphocytes circulating in the
lymph nodes of both B-cell lymphomas and Hodgkin disease suggested
TTV infection implication in the development of these
Recently, Camci et al. has reported the high prevalence of
TTV in patients with various malignancies.
The viral load in cancer patients is extremely high. It might result
from the impaired immune reaction[1,15].
Further studies are needed to explain whether the impairment is
caused by neoplasm or by the virus itself.
The cases of coexistence of TTV infection and
pancreas cancer presented above should be treated as a preliminary
report and the comment in the discussion about the real role of TTV
in human pathology. Since the virus may infect the pancreatic tissue
and the pathogenesis of pancreas cancer has not been completely
cleared many factors, including infectious agent(s) should be
considered in the oncogenesis study. Two case reports are not enough
to draw any conclusions. We believe that further research on
possible link between hepatitis or other pathology and TTV
infection, is needed.
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