ORIGINAL ARTICLE
TT Virus Infection in Patients with Primary Hypogammaglobulinaemia:
Natural History and Relationship to Liver Disease in the
Immunocompromised Host
K. Bjøro, E. P. Petrova, M. G. Thomas, S. S. Frøland, R. Williams & N. V. Naoumov
Dept. of Medicine, National Hospital, Oslo, Norway; Institute of Hepatology , Depts. of Medicine and
Biology, University College London, London, United Kingdom
Bjøro K, Petrova EP, Thomas MG, Frøland SS, Williams R, Naoumov NV. TT virus infection in patients
with primary hypogammaglobulinaemia : natural history and relationshi p to liver disease in the
immunocompromised host. Scand J Gastroenterol 2001;36:98 7–993.
Background: TT virus (TTV) is a recently discovere d human DNA virus with worldwide distribution ,
but with no clear disease association . The possibilit y of an enhance d TTV virulence in patients with
immunodeŽ ciencies has not yet been investigate d but is of particula r interest because other viruses have
been demonstrate d to cause severe and rapid liver disease in such patients. Here we analysed the
characteristic s of TTV infection in a large cohort of patients with primary hypogammaglobulinaemi a
(PHG) and whether TTV has a role in the frequentl y observed cryptogeni c liver disease in these patients.
Methods: 83 Norwegian patients with PHG (serum immunoglobuli n G < 2 g/L), receiving substitution
treatment with immunoglobulins , were followed regularly for median 10.2 years (range 2–30). TTV DNA
was sought in serum samples and three immunoglobuli n preparation s by polymerase chain reaction; TTV
DNA quantitation , DNA sequencin g and phylogeneti c analysis were performed in selected samples.
Results: TTV DNA was detected in 27 of 83 (32.5%) patients and was not associate d with a particula r
type of PHG. The prevalence of TTV infection was dependen t on intravenou s immunoglobuli n
administration , duration of therapy and patient’s age. TTV DNA was found in two of three currently used
immunoglobuli n preparations . In the longitudina l study, whether TTV was cleared or newly acquired had
no impact on liver function tests and no particula r TTV strain was found in patients with more severe
liver disease. Conclusions: TTV infection is common in patients with PHG. Treatment with
immunoglobulin s has a role in the transmission of TTV in these patients. However, we found no
evidence of TTV-induced liver disease in this group of immunocompromise d patients.
Key words: Hepatitis; hypogammaglobulinaemia ; immunodeŽ ciency; immunoglobulins ; TTV
Kristian Bjøro, Section for Hepatology and Gastroenterology , Dept. of Medicine, National Hospital,
University of Oslo, NO-0027 Oslo, Norway (fax. ‡47 23 07 04 51, e-mail. kristian.bjoro@labmed.uio.no )
I
Ó
n 1997, the search for a causative agent of cryptogenic
hepatitis led to the identiŽ cation of a novel human DNA
virus, named TT virus (TTV) (1). Studies on TTV
characteristics revealed that the viral genome is circular,
single-stranded DNA comprising 3,852 nucleotides, with no
identity to other viruses, thus suggesting that TTV is a
member of a new virus family that infects humans (2, 3).
Initially, TTV DNA was ampliŽ ed from serum samples from
three patients with post-transfusion hepatitis of unknown
aetiology (1). Based on these Ž ndings and on the high
prevalence of TTV infection in Japanese patients with
fulminant hepatitis and chronic liver disease of unknown
aetiology, TTV was suggested as the causative agent for some
cryptogenic liver diseases (1, 4). However, TT viraemia was
detected in a large proportion of healthy subjects and in
patients with no biochemical or histological evidence of
hepatitis and it was proposed that TTV does not cause liver
2001 Taylor & Francis
diseases (5). Subsequent studies demonstrated that TTV
infection has a worldwide distribution with a high prevalence
in healthy people such as blood donors—in the USA between
7.5% and 13% (6, 7); in Japan 35%–37% (8, 9); in Germany
and Spain 7% and 14% (10, 11); as well as in rural
populations in tropical countries—74% in Papua New Guinea
and 83% in the Gambia (12). The pathogenic role and clinical
signiŽ cance of TTV infection remain unclear, as these
investigations found no clear correlation with hepatitis or
liver damage.
The role of TTV in patients with primary hypogammaglobulinaemia is of particular interest because hepatitis C virus
infection (HCV) has been demonstrated to be both prevalent
and to run a very severe clinical course in these patients
(13, 14). Liver disease is a frequent complication in a
substantial proportion of cases of unknown aetiology (15).
Non-A, non-B hepatitis has been reported after intravenous
988
K. Bjøro et al.
Table I. Distribution of patients with primary hypogammaglobulinaemi a according to the presence of liver disease
Type of primary hypogammaglobulinaemi a
1. Common variable immunodeŽ ciency
2. Congenital hypogammaglobulinaemi a
3. X-linked agammaglobulinaemi a (Bruton’s type)
4. Hyper-IgM syndrom e
TOTAL
HCV RNA‡
liver disease
Non-B, non-C
liver disease
Non-B, non-C
no liver disease
Total
7
5
6
2
20
22
2
0
0
24
23
15
1
0
39
52
22
7
2
83
administration of immunoglobulin s (13, 16–18) and hepatitis
C virus (HCV) has been detected in some immunoglobulin
preparations (19).
The aim of the current study was to test the hypothesis that
TTV is responsible for cryptogenic liver disease in patients
with primary hypogammaglobulinaemia. In a large group of
well-characterized patients we determined the presence of TT
viraemia and investigated the clinical course of TTV infection
and liver disease in a longitudinal study of TTV-positive
patients. In addition, we assessed the presence of TTV in
currently used immunoglobulin preparations.
Materials and Methods
Selection of patients and serum samples
Eighty-three patients with PHG, followed regularly (median 10.2 years, range 2.9–30 years) at the Section of Clinical
Immunology and Infectious Diseases, Dept. of Medicine,
Rikshospitalet, National Hospital, Oslo were included in the
study. These patients fulŽ lled the following inclusion criteria:
1) at least one serum sample available for analysis; 2) known
history of substitution therapy with immunoglobulin in any
form; 3) documented follow-up with clinical and laboratory
investigations for the presence of liver disease. All patients
included in the study were Caucasians (50 men and 33
women). The median age at the last visit was 44 years (range
14–76). Depending on the presence of liver disease, patients
with PHG formed 3 subgroups: 20 patients with HCV-related
liver diseases; 24 patients with non-B, non-C liver disease;and
39 patients with no liver disease (Table I).
The diagnosis of PHG was based on established criteria
(20). The type of antibody deŽ ciency was classiŽ ed as
described previously (22): 1) common variable immunodeŽ ciency (n = 52); 2) congenital hypogammaglobulinaemia
(n = 22); 3) X-linked agammaglobulinaemia (Bruton’s type)
(n = 7); 4) hyper-IgM syndrome (n = 2) (Table I). All 83
patients had serum IgG levels below 2.0 g/L before the
substitution therapy was initiated. The median duration of
immunoglobulin therapy was 12.4 years (range 1.6–43 years).
Thirty-one of 83 patients have received one or more different
commercial preparations of intravenous immunoglobulins
(IVIG). For the last 8–10 years the great majority of patients
have been substituted by immunoglobulin preparations
administered subcutaneously (23). Only a minority of the
patients studied had other risk factors for parenterally
Scand J Gastroenterol 2001 (9)
acquired infections—a history of intravenous drug use
(n = 2); tattoos (n = 3); transfusions of erythrocytes or
platelets (n = 5).
The monitoring for liver disease was performed in all
patients at least twice per year. This comprised clinical
examination, liver function tests (serum alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase,
bilirubin, albumin) and coagulation. Patients were classiŽ ed
as having liver disease if one or more of the parameters tested
were abnormal (>1.5 times upper limit of normal) in at least
three subsequent samples obtained over a period of 6 months.
Patients with PHG who had persistently normal LFTs during
the entire follow-up period and no abnormality on the
imaging investigations were classiŽ ed as patients with no
liver disease. Ultrasound examination of the liver and spleen
was performed regularly in all patients and most patients had
a CT-scan of the abdomen. Liver biopsy or endoscopic
retrograde cholangio-pancreatography were performed when
clinically indicated.
The Ž rst available serum sample from the 83 patients
included in the study was tested for TTV DNA. In all cases,
these samples were obtained after starting the substitution
therapy with immunoglobulins . Serial serum samples from 25
patients who were found to be TTV positive (between 2 and 5
samples per patient, obtained over a period of 2–6 years) were
also tested for TTV DNA. In addition, serial samples,
collected over a period of 2–6 years, from 12 patients, who
were initially TTV negative were also analysed for newly
acquired TTV infection. All samples used in this study were
stored at ¡70 °C.
As a control group we investigated the presence of TTV
infection in 20 Norwegian patients with autoimmune chronic
liver disease—autoimmune hepatitis (n = 10); primary biliary
cirrhosis (n = 6) and primary sclerosing cholangitis (n = 4).
Only 2 of these 20 patients had received blood transfusions
and none had a history of intravenous drug use or therapy with
immunoglobulins.
Immunoglobulin reparations
Three different preparations currently used for substitution
therapy were available to test for TTV DNA. Gammanorm
(Pharmacia-Upjohn, Stockholm, Sweden) has been used for
subcutaneous administration from 1996 and is produced from
Scandinavian blood donors. The immunoglobulin s were
fractionated in accordance with Cohn et al. (24). The
TTV in Primary Hypogammaglobulinaemi a
989
preparation was treated with Tris-n-butyl-phosphat e and
Tween 80, as virus inactivation. Gammaglobulin (Pharmacia-Upjohn, Stockholm, Sweden) has been used for intramuscular and subcutaneous administration since 1968. The
preparation was obtained from European blood donors.
Fractionation and virus inactivation were as described above.
Octagam (Octapharma, Vienna, Austria) was obtained from
Norwegian blood donors and has been used intravenously
since 1994. In addition to the fractionation and virus
inactivation steps described for the other two preparations,
Octagam production includes incubation at pH 4.0.
Serological assays
All serum samples were tested for markers of HBV
(HBsAg), HCV (anti-HCV and HCV RNA) and HGV
(HGV RNA), as previously reported (13, 17).
Detection and analysis of TTV DNA
All samples were tested for TTV DNA in duplicate, which
was performed blindly with respect to any information
regarding the sample or the patient. TTV DNA was sought
by semi-nested PCR, as previously described (4, 5). Brie y,
total DNA was extracted from 100 mL serum using QIAamp
Blood kit (QIAGEN Ltd, Crawley, UK) and resuspended in
50 mL elution buffer. For the Ž rst round PCR, a sense primer
NG059 (5’-ACA GAC AGA GGA GAA GGC AAC ATG-3’)
and an antisense primer NG063 (5’-CTG GCA TTT TAC
CAT TTC CAA AGT T-3’) were used. The ampliŽ cation was
for 35 cycles at 94 °C for 30 sec, 58 °C for 30 sec and 72 °C
for 60 sec, followed by 7 min at 72 °C after the last cycle. The
second round was performed with a sense primer NG061 (5’GGC AAC ATG TTA TGG ATA GAC TGG-3’) and NG063
as an antisense primer for 35 cycles at the same conditions.
The amplicons were electrophoresed in 2% agarose gel,
stained with ethidium bromide and photographe d under
ultraviolet light.
The serum level of TTV DNA was quantitated in selected
PHG patients with and without liver diseases and compared
with TT viraemia in randomly selected healthy subjects. The
level of TTV DNA was assessed by ampliŽ cation of serial
end-point dilutions of a standard amount of DNA extracted
from the serum. Serial dilutions of a known TTV DNA
positive sample were used as a positive control. The results
were expressed as DNA copies/mL, as previously described
(25).
To gain information about the changes in the TTV
population over time in patients with PHG, serial samples
from four TTV-positive patients were analysed by direct
DNA sequencing. In addition, DNA sequencing analysis was
performed for TTV DNA ampliŽ ed from the immunoglobulin
preparations. The amplicons were puriŽ ed with the QIAquick
PCR puriŽ cation kit (QIAGEN Ltd) and sequenced on an ABI
377 automated sequencer (PE Applied Biosystems) with
NG061 as a sequencing primer. Phylogenetic analysis was
carried out using the PHYLIP package (26). A distance tree
was constructed using the DNADIST and NEIGHBOR
programs. Distances were calculated according to the twoparameter method of Kimura (27), assuming a transition/
transversion ratio of 10, and the phylogenetic tree constructed
using the UPGMA algorithm.
Prevalence of TTV in primary hypogammaglobulinaemi a
TTV DNA was detected in the earliest serum sample tested
from 27 of 83 (32.5%) patients. The presence of TTV
infection was not associated with any particular type of
hypogammaglobulinaemia . Of the 27 TTV-positive patients,
15 had common variable immunodeŽ ciency, 6 congenital
hypogammaglobulinaemia , 4 had X-linked agammaglobulinaemia and 2 hyper IgM syndrome. The comparison between
TTV DNA-positive and -negative patients revealed that
seropositivity for TTV DNA is associated with intravenous
administration of immunoglobulins, the duration of substitution treatment and patient’s age (Table II). Eighteen of 27
TTV positive patients have received immunoglobulin s
intravenously, in contrast to only 10 of 58 TTV negative
patients (P = 0.002). Among all patients who were negative
for HCV and HBV markers with and without liver disease
(n = 63), the TTV-positive cases had signiŽ cantly longer
duration of immunoglobulin therapy than TTV-negative
cases—median 16 years (range 6–45) versus 11 years (2–
31), respectively (P = 0.009; Table II). Within the subgroup of
patients with non-B, non-C liver disease (n = 24), those with
TTV infection were signiŽ cantly older (median 58 years,
range 29–81) than TTV-negative cases (median 33 years,
range 23–55) (Table II; P = 0.004). There was no signiŽ cant
age difference between TTV-positive and -negative cases in
the other two subgroups, although the number of TTV DNApositive cases amongst 39 patients with no liver disease was
too small (Table II). In the control group, 3 of 20 (15%)
patients with autoimmune liver diseases were TTV DNApositive.
Statistical analyses
Comparisons between groups were performed using the
Wilcoxon non-parametric test or chi-squared test with Yates’
correction, where appropriate.
Results
Liver disease in patients with primary
hypogammaglobulinaemia
TTV infection was found in 11 of 18 (61%) HCV RNApositive patients; in 12 of 24 (50%) patients with non-B, nonC liver disease and in 4 of 39 (10%) patients with no liver
disease (Table II). The HCV RNA-positive patients contracted the infection in 1984–86 through HCV-contaminated
immunoglobulin (Gammonativ) (12). Five of 11 patients who
were HCV RNA and TTV DNA-positive died of end-stage
cirrhosis and liver failure within 12 years of acquiring HCV
infection. The other six patients have liver disease of varying
severity, with cirrhosis in two. All nine HCV RNA-positive
Scand J Gastroenterol 2001 (9)
990
K. Bjøro et al.
Table II. Risk factors for TTV infection in patients with primary hypogammaglobulinaemi a
History of IVIG
Duration of Ig therapy (years—median, range)
Age (years—median, range)
HCV RNA-positive
(n = 20)
Non-B, non-C liver
disease (n = 24)
No liver disease
(n = 39)
TTV
(n = 11)
‡ TTV-ve
(n = 9)
TTV‡
(n = 12)
TTV-ve
(n = 12)
TTV‡
(n = 4)
TTV-ve
(n = 35)
11/11
18(16–45)
32(19–59)
9/9
16(13–20)
28(20–68)
6/12
14(3–31)
58(29–81)
1/12
11(3–18)
33(23–55)
1/4
11(6–14)
36(21–59)
0/35
5a (2–19)
39(14–74)
Duration of Ig therapy includes all routes of IgG administration —intravenous , subcutaneou s and intramuscular .
a
IgG was given only via non-intravenou s routes, mainly subcutaneous .
patients with no TTV infection also had liver disease; three of
these died with end-stage cirrhosis and three from unrelated
causes. Among 12 patients with non-B, non-C liver disease
and TTV infection, none had a history of acute hepatitis.
Serum ALT and alkaline phosphatase were moderately
elevated in these patients, while the synthetic liver function
was normal with no evidence of cirrhosis. One patient had
granulomatous hepatitis on liver biopsy, which progressed to
cirrhosis during the last 8 years.
TTV DNA titres did not differ between PHG patients with
or without liver disease or healthy controls.
Longitudina l follow-up of TTV infection and liver disease
Between 2 and 5 serial serum samples were available from
25 of 27 TTV DNA-positive patients. Seventeen of 25
patients were TTV DNA-positive in all samples, while in 8
patients TTV DNA was not detectable in the follow-up
samples (Fig. 1). Among 12 patients who were TTVnegative in the Ž rst sample, 2 became positive in a later
sample (case nos. 16 and 17; Fig. 1A), while the other 10
remained TTV-negative. One of these two cases (no. 17; Fig.
1A) had established cirrhosis in 1993 prior to becoming TTV
DNA-positive. During the follow-up, the liver damage
progressed to decompensated cirrhosis with low albumin,
prothrombin time and increased bilirubin. Five patients with
PHG showed no evidence of liver diseases despite being
TTV DNA-positive (Fig. 1A, case nos. 4, 7, 9, 14 and 16).
The liver function tests in patients with non-B, non-C liver
disease and TTV infection over time showed no signiŽ cant
changes with mild to moderate (<3 £ ULN) increase of
serum ALT and/or alkaline phosphatase. During the followup, three patients with non-B, non-C liver disease (Fig. 1A)
and three HCV RNA-positive patients (Fig. 1B) lost TTV
DNA from the serum. The clearance of TTV in these
patients was not associated with normalization or improvement in the liver function tests.
To analyse the changes of TTV population over time in
patients with PHG, TTV DNA was ampliŽ ed and sequenced
from serial serum samples of patients with the longest followup—patient nos. 1, 5 and 8 (Fig. 1A) and patient no. 20 (= 3 in
Fig. 1B). There was no nucleotide variation in the 200 base
region of the TTV genome in all 4 samples, collected over a 6Scand J Gastroenterol 2001 (9)
year period, from case no. 8. This patient had common
variable immunodeŽ ciency and severe granulomatous hepatitis which progressed to cirrhosis during the observation
period. The TTV population also remained unchanged in case
no. 20, as TTV DNA in one of the samples differed by only
two nucleotides from the other three samples which had
identical sequences. Phylogenetic analysis revealed a signiŽ cant evolutionary distance between TTV DNA in the sera
taken at different time points from the other two cases (Fig.
Fig. 1. Longitudina l follow-up of patients with primary hypogammaglobulinaemi a (PHG) with respect to the detection of TTV DNA
in serum (‡) or loss of TT viraemia (¡). The grey bars indicate the
presence of liver disease, while the white bars indicate no liver
disease. *Patients with histologicall y proven cirrhosis. a) PHG
patients without markers for HBV or HCV infection (non-B, non-C
cases). b) PHG patients who are HCV RNA-positive. CVI: common
variable immunodeŽ ciency; CH: congenital hypogammaglobulinae mia; XLA: X-linked agammaglobulinaemia ; HIM: hyper-Ig M
syndrome.
TTV in Primary Hypogammaglobulinaemi a
991
Fig. 2. Phylogenetic analysis of TTV isolates from serial samples of patients with primary
hypogammaglobulinaemi a collected over a period of 3 to 6 years and from two immunoglobuli n
preparations . Patient numbers (1, 5, 8 and 20) are the same as shown in Fig. 2. S1 to S4 indicate serum
samples taken at different time points from a particula r patient. Ig-Gam 1 and 2: two batches of
Gammanorm; IgG-Oct1-3: three batches of Octagam. The branch lengths are proportiona l to the genetic
distance (scale shown).
2). The Ž rst two samples from patient no. 1 contained almost
identical viral population, which was related to the originally
described TTV genotype 1 (4). The serum taken 6 years later
showed predominance of TTV population with >30%
nucleotide differences and close to genotype 2. Importantly,
the new TTV strain in this patient is similar to the virus
present in patient no. 8, who has severe liver disease (Fig. 2).
The predominance of this new TTV strain was not associated
with changes in the liver function tests. SigniŽ cant differences
were also found in the TTV population in serum samples
taken 5 years apart from patient no. 5 (Fig. 3). The changes in
TTV population from one to another genotype over time in
the last two cases were not associated with changes in the
degree of liver damage.
TTV DNA in immunoglobuli n preparations
Three commercial preparations of immunoglobulin s were
tested for TTV DNA: three different batches of Octagam
(Octapharma), two batches of Gammaglobulin (Pharmacia
Upjohn) and two batches of Gammanorm (Pharmacia
Upjohn). TTV DNA was detected in all batches of Octagam
and Gammanorm, while both batches of Gammaglobulin
were negative. DNA sequencing analysis of the amplicons
showed no variations within the ampliŽ ed region (Fig. 2). The
TTV type in the immunoglobulin s belonged to genotype 2,
showing 11% nucleotide variability in comparison to genotype 2a (4). The same TTV genotype was found in the
majority of samples tested (Fig. 2).
Discussion
TTV is a recently discovered human DNA virus with no
clear disease association. In the present study we investigated a possible role of TTV in the development of liver
disease in a large group of patients with primary hypogammaglobulinaemia followed for a median period of 10.2 years.
The results show that TTV infection is highly prevalent in
these patients and that substitution treatment with immunoglobulins, especially intravenous administration, represents
an important route for acquiring TTV in this group. The
longitudina l analysis revealed that one-third of patients with
TT viraemia can clear the virus spontaneously over a period
of 2–6 years, while TTV DNA remains detectable in the
serum in the majority of patients. Despite viral persistence,
we found no strong evidence that TTV is responsible for
cryptogenic liver disease in patients with primary hypogammaglobulinaemia.
Viral infections in immunocompromised host are frequently associated with signiŽ cant morbidity. Chronic HCV
infection in patients with primary hypogammaglobulinaemia
or in HIV-infected patients has a severe course with rapid
progression to cirrhosis (14, 28). Although TT viraemia was
more frequent in PHG patients with non-B, non-C hepatitis
than in patients without liver disease, a careful analysis shows
no causative relationship. Firstly, we found no speciŽ c viral
characteristics (high level of viraemia or a particular TTV
strain) in PHG patients with non-B, non-C hepatitis; secondly,
patients who cleared TTV during the follow-up showed no
Scand J Gastroenterol 2001 (9)
992
K. Bjøro et al.
resolution of liver disease; thirdly, there was no difference in
the severity of liver disease in patients co-infected with HCV
and TTV and those with HCV alone; Ž nally, the higher
prevalence of TTV infection in patients with non-B, non-C
hepatitis was associated with differences in age, intravenous
use of immunoglobulin s and a longer duration of substitution
therapy. These Ž ndings in immunosuppressed patients extend
a large body of evidence in patients with cryptogenic hepatitis
with no immunodeŽ ciencies suggesting that chronic TTV
infection has no pathogenic role for liver disease
(5, 8, 10, 11).
Our data provide further evidence that TTV is transmitted
parenterally. The viral genome was detected in several
batches of human immunoglobulin preparations, treated
with ‘state of the art’ methods for viral inactivation, and the
prevalence of TTV infection correlated with the use of
immunoglobulin s intravenously and the duration of treatment.
A strong association between the volume of transfused blood
or blood products and TTV infection was shown in healthy
subjects and in patients with haemophilia (6, 25). In addition,
our study shows that TT viraemia persists for years in the
majority of patients with primary hypogammaglobulinaemia .
A similarly high rate of TTV persistence was also observed
during a follow-up of multi-transfused patients (28). We
observed spontaneous TTV clearance in 32% of patients,
which is lower than the rate of TTV clearance (67%) reported
in normal subjects with newly acquired TTV infection (6).
The great diversity of viral population is a characteristic
feature of TTV and co-existence of several TTV genotypes
has been shown in healthy subjects and in multi-transfused
patients (2, 30). On this basis, it is difŽ cult to establish
whether the marked changes in TTV population over time in
two of our patients re ected the co-existence of more than one
TTV genotype or repeated infections; however, as the
differences in DNA sequence are considerable, these changes
are not due to simple mutations.
In summary, the present study demonstrates that TTV
infection is very common in patients with primary hypogammaglobulinaemia. The substitution therapy with immunoglobulins, especially intravenous administration, has a signiŽ cant
role for transmitting TTV and the virus persists in the majority
of patients. In this large cohort of well-characterized and
prospectively followed patients with primary hypogammaglobulinaemia we found no strong evidence that TTV can
cause liver disease in immunocompromised patients.
Acknowledgements
This study was supported in part by a grant from the Trustees
of the Middlesex and University College Hospitals, London.
Elena Petrova was a recipient of a NATO Postdoctoral
fellowship from the Royal Society, UK. Mark Thomas is
supported by the Melford Charitable Trust. Bodil Lunden is
greatly acknowledged for skilful help with the blood samples.
Scand J Gastroenterol 2001 (9)
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Received 17 January 2001
Accepted 29 January 2001
Scand J Gastroenterol 2001 (9)