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1 All authors: Medizinische Klinik II, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt au Main, Germany.
Received April 16, 1999;
accepted after revision August 24, 1999.
Address correspondence to S. Zeuzem.
Abstract
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SUBJECTS AND METHODS. In 59 patients with chronic hepatitis C infection, the total perihepatic lymph node volume was assessed using sonography before the initiation of antiviral treatment, at the end of treatment, and at the end of a 6-month follow-up period. Hepatitis C viremia was assessed by reverse transcription—polymerase chain reaction assay at the same time points. Liver biopsy was performed in all patients before therapy and in 40 of the 59 patients 6 months after therapy.
RESULTS. At the end of follow-up, the total perihepatic lymph node volume was significantly smaller in the 15 patients with a sustained virologic response than in the 44 patients who failed to respond to treatment (0.5 ± 0.3 ml versus 2.0 ± 1.2 ml; p<0.0001). In the group of sustained virologic responders, the decline of the perihepatic lymph node volume was associated with an improvement in liver histology.
CONCLUSION. Total perihepatic lymph node volume changes according to the antiviral response and leads to progressive normalization of the perihepatic lymph node volume in sustained virologic responders. A decrease in the perihepatic lymph node volume is associated with an improvement in liver histology.
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alone or in combination with
ribavirin can achieve clearance of hepatitis C virus from serum and liver,
which is associated with a substantial improvement in liver histology
[2,3]. Lymph nodes are detectable within the hepatoduodenal ligament in almost all patients with chronic hepatitis C and adequate sonographic visualization of the liver hilus [4,5,6,7,8]. The sonographically determined total perihepatic lymph node volume corresponds to viremia and liver histology. Patients with severe histologic inflammation or high virus load show a larger total perihepatic lymph node volume than those with only mild to moderate inflammatory activity within the liver or low viremia [5]. The mechanism of portal lymphadenopathy, however, is unknown but appears to be related to viral replication within the liver and the immune-mediated inflammatory response of the host [5].
Sonographic evaluation of total perihepatic lymph node volume may be a parameter that enables prediction of and that reflects antiviral response and may replace the necessity of a liver biopsy after antiviral therapy. In this study we determined the perihepatic lymph node volume before initiation of antiviral therapy, at the end of treatment, and at 6-month follow-up.
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Forty-one patients were treated with 3 x 106 U of
interferon- alone subcutaneously thrice weekly for 6-12 months, and 18
patients received combination therapy with 3 x 106 U
interferon- subcutaneously thrice weekly plus ribavirin (1000-1200
mg/day according to body weight) for 6-12 months
(Table 1). Eighteen of the
patients treated with interferon- and all the patients treated with
combination therapy were treated within a placebo-controlled and randomized
trial. In all patients, lymph node status within the hepatoduodenal ligament
and the virologic response were assessed at the end of treatment and at the
end of a 6-month follow-up period. Forty (68%) of 59 patients consented to a
second sonographically guided liver biopsy, which was performed at the end of
the follow-up period.
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Ten age-matched healthy volunteers (Seven men and three women; age range, 22-61 years; mean age, 40 ± 11 years) participated in the study as control subjects; the liver hilus was prospectively examined by transabdominal sonography at 6-month intervals. For all healthy subjects, findings of liver function tests were within the normal range at the beginning and end of the study period; chronic liver diseases (infectious, metabolic, toxic, autoimmune, hereditary) were excluded using appropriate bio-chemical and serologic tests. Adequate sonographic visualization of the hepatoduodenal ligament was achieved in all healthy subjects.
The study was conducted according to the Declaration of Helsinki. All patients and healthy subjects were at least 18 years old, and informed consent was obtained.
Definition of Response
Treatment response was defined on the basis of hepatitis C—virus RNA
testing by reverse transcription—polymerase chain reaction assay at the
end of treatment (end-of-treatment response) and at the end of the follow-up
period (sustained virologic response). In relapse patients, hepatitis
C—virus RNA was undetectable at the end of treatment but reverse
transcription—polymerase chain reaction assay became positive during
follow-up. Patients with detectable hepatitis C—virus RNA during and at
the end of treatment were considered nonresponders.
Detection of Lymph Nodes in the Hepatoduodenal Ligament Using
Transabdominal Sonography
As previously described, lymph nodes in the hepatoduodenal ligament can be
noninvasively detected using modern imaging techniques such as sonography
[4,5,6,7,8].
In all patients and healthy subjects, the number and size of all detectable
perihepatic lymph nodes were determined. The size of each lymph node was
measured in the longest axis (a) and in the corresponding perpendicular axis
(b), respectively. Individual lymph node volume was calculated assuming a
(rotating) ellipsoid (volume = a/2 x [b/2]2 x 4/3
). The volumes of individual lymph nodes within the hepatoduodenal
ligament were subsequently summarized and expressed as total perihepatic lymph
node volume. Perihepatic lymph nodes of all patients and healthy subjects were
assessed by the same experienced investigator who was unaware of biochemical
and histologic data. All sonographic examinations were performed with a 3.5-
or 5.0-MHz probe using a high-resolution B-mode scanner (Model 128; Acuson,
Mountain View, CA). The reproducibility of the method was previously
investigated by repeated sonographic examinations of the lymph nodes in the
hepatoduodenal ligament in 10 healthy subjects for 7 consecutive days. The
mean coefficient of variation for intraindividual assessment of perihepatic
total lymph node volume was 12%
[5].
Histologic Evaluation
All specimens were prepared as previously described
[5,9,10]
and examined by an experienced pathologist who was unaware of biochemical and
virologic data and lymph node status within the hepatoduodenal ligament. Liver
histology was semiquantitatively evaluated using the histologic activity index
(HAI) described by Knodell et al.
[9].
Serologic and Molecular Laboratory Tests
Testing for anti—hepatitis C virus antibodies (second generation),
hepatitis B surface antigen, hepatitis B core antibodies, or anti-HIV
antibodies 1 and 2 was performed using commercially available enzyme-linked
immunosorbent assays. Blood samples for molecular tests were centrifuged
within 2 hr to achieve optimal conditions for hepatitis C-virus RNA
determination. Detection of hepatitis C-virus RNA by reverse
transcription—polymerase chain reaction and hepatitis C virus genotyping
by reverse hybridization assay (Inno-Lipa HCV II; Innogenetics, Gent, Belgium)
was performed essentially as previously described
[5,10,11,12,13].
Statistical Analysis
Clinical and biochemical characteristics of patients were expressed as mean
± SD. Relationships between variables were examined using Spearman's
rank correlation coefficient. All p values were tested using the
Mann-Whitney test and Wilcoxon's rank sum test to compare data before and
after treatment; a p value of less than 0.05 was judged to be
statistically significant.
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without or in combination with ribavirin. The clinical,
biochemical, molecular, and histologic pretreatment characteristics are
summarized in Table 1. In 38
(64%) of 59 patients, hepatitis C—virus RNA remained detectable during
treatment (virologic nonresponders), whereas in six (10%) of 59 patients,
hepatitis C—virus RNA was undetectable at the end of treatment but
relapse occurred within the 6-month follow-up period. Fifteen (25%) of 59
patients achieved a sustained virologic response (i.e., hepatitis
C—virus RNA was undetectable at the end of treatment and follow-up
period). Most of the sustained virologic responders (n = 8) were infected with hepatitis C virus—genotype 3, but five hepatitis C virus—genotype 1 infected patients achieved sustained hepatitis C—virus RNA clearance. In the group of virologic nonresponders, most patients (n = 29) were infected with hepatitis C—virus genotype 1 (Table 1). Pretreatment viremia was lower in 15 sustained virologic responders than in 44 relapsers or nonresponders (2.1 ± 2.5 [range, 0.1-8.5] x 106 copies/ml versus 5.3 ± 7.4 [range 0.1-48] x 106 copies/ml, respectively; p<0.05) (Table 2).
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Before treatment was initiated, liver biopsy was performed in each patient (Table 1), whereas after treatment ended, only 40 of the 59 patients consented to a second biopsy 6 months after treatment (Table 3). The total HAI of the patients with a paired liver biopsy available declined from 9.7 ± 3.5 (range, 2-15) before treatment to 7.1 ± 4.1 (range, 1-15) at the end of the follow-up period (p<0.001). A significant improvement was observed for the inflammatory parameters of the HAI (HAI I-III: 7.2 ± 2.7 [range, 1-11] versus 4.7 ± 3.1 [range 1-11]; p<0.001), whereas a trend toward an improvement was only found for the fibrosis score (HAI IV: 2.5 ± 1.1 [range, 1-4] versus 2.2 ± 1.3 [range, 1-4]; p = 0.1). The most pronounced decline of the total HAI was observed within the group of sustained virologic responders (Figs. 1 and 2).
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Lymph nodes within the hepatoduodenal ligament were detectable in seven (70%) of the 10 healthy subjects and in all patients with chronic hepatitis C before, at the end of, and after treatment. Sonography of the lymph nodes within the hepatoduodenal ligament before and at the end of treatment in patients with a sustained virologic response showed enlarged perihepatic lymph nodes before treatment and normalization of lymph node size at the end of treatment (Fig. 3A,3B). The total perihepatic lymph node volume in the healthy, subjects was 0.3 ± 0.3 ml (range, 0-0.6 ml) and remained constant during the 18-month observation period. In patients with chronic hepatitis C, the total perihepatic lymph node volume before initiation of treatment was 2.1 ± 1.5 ml (range, 0.5-6.0 ml) compared with 1.7 ± 1.2 ml (range, 0.4-5.8 ml) at the end of treatment and 1.6 ± 1.2 ml (range, 0.1-4.9 ml) at the end of follow-up. A trend was observed in which patients with a sustained virologic response had a smaller pretreatment total perihepatic lymph node volume compared with 44 virologic relapsers and nonresponders (1.6 ± 1.4 ml versus 2.3 ± 1.5 ml, respectively; p = 0.05). The mean total lymph node volume within the hepatoduodenal ligament before initiation of therapy, at the end of treatment, and after the posttreatment follow-up period was 1.6 ± 1.4 ml, 0.8 ± 0.5 ml, and 0.5 ± 0.3 ml in sustained virologic responders; 1.6 ± 0.3 ml, 1.7 ± 0.8 ml, and 1.8 ± 0.4 ml in patients with a virologic end-of-treatment response but relapse thereafter; and 2.4 ± 1.6 ml, 2.0 ± 1.3 ml, and 2.0 ± 1.2 ml in virologic nonresponders, respectively (Figs. 4,5,6). Thus, a significant decline of the total perihepatic lymph node volume was observed only in the group of patients with a sustained virologic response (Table 2).
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The total perihepatic lymph node volume at the end of treatment was significantly higher in relapse patients than sustained virologic responders (1.7 ± 0.8 ml versus 0.8 ± 0.5 ml; p<0.001). At the end of the follow-up period, the total perihepatic lymph node volume was less than 1.2 ml in all sustained virologic responders and the decline of the total perihepatic lymph node volume was associated with an improvement in the HAI. The mean total perihepatic lymph node volume in the group of sustained virologic responders was, however, slightly higher at the end of the follow-up period compared with that of the healthy subjects (0.5 ± 0.3 ml versus 0.3 ± 0.3 ml; p<0.05).
The decline of the total perihepatic lymph node volume, expressed as the relation of the end-of-follow-up and pretreatment perihepatic lymph node volumes, was 0.4 ± 0.3 (range, 0.1-1) in sustained responders compared with 1.0 ± 0.6 (range, 0.3-2.6) in nonresponders and 1.2 ± 0.4 (range, 0.7-2.1) in patients with an end-of-treatment response but relapse. Assuming a reduction of the perihepatic lymph node volume of more than 20% as a marker of sustained antiviral response, the sensitivity was 1.0 and the specificity 0.3 (positive predictive value, 0.8; negative predictive value, 1.0). Assuming a reduction of the perihepatic lymph node volume of more than 50% (pretreatment versus end of follow-up), sensitivity decreased to 0.8 with a specificity of 0.5 (positive predictive value, 0.8; negative predictive value, 0.5).
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Lymph nodes within the hepatoduodenal ligament were detected in all 59 patients infected with the hepatitis C virus before, at the end of treatment, and at the end of a 6-month follow-up period. In the 15 patients who achieved a sustained virologic response after antiviral treatment, the total lymph node volume in the hepatoduodenal ligament at the end of the follow-up period was significantly smaller compared with that in patients without sustained virologic response. In all patients with sustained virologic response, the total perihepatic lymph node volume was less than 1.2 ml at the end of the follow-up period. The absolute value of lymph node volume after treatment rather than the change in lymph node volume, expressed as the decline in percentage of the pretreatment size, appears to be helpful for patient treatment. Patients with an end-of-treatment virologic response and relapse within the 6-month follow-up period revealed a larger total perihepatic lymph node volume at the end of treatment than sustained virologic responders. Therefore, determination of the total perihepatic lymph node volume at the end of treatment may be a marker for relapse. It is conceivable that this is related to residual virus replication in the liver or in extrahepatic sites such as lymphocytes.
The results of our study confirm those of previous studies that histologic improvement is more pronounced in sustained virologic responders than in nonresponders and relapse patients [2, 3, 14]. In patients with chronic hepatitis C, sonographic assessment of lymph nodes within the hepatoduodenal ligament revealed a correlation between the total perihepatic lymph node volume and HAI. Patients with severe histologic inflammation showed a larger total perihepatic lymph node volume than those with only mild to moderate inflammatory activity [5]. Our findings show that the total perihepatic lymph node volume also reflects histologic improvement in patients treated for chronic hepatitis C. The recommendation to replace liver biopsy after treatment with sonographic assessment of the hepatoduodenal ligament may be preliminary. However, the assessment of the perihepatic lymph node volume is noninvasive and can easily be repeated. Especially in cases with discrepant results in the perihepatic lymph node volume and the viremia status, liver biopsy appears necessary. The mechanism of portal lymphadenopathy in patients with chronic hepatitis C is unknown. Changes of the total perihepatic lymph node volume in patients with chronic hepatitis C during antiviral therapy could be caused by changes in viral replication and intra- or extrahepatic cellular or humoral immunologic mechanisms.
Results of several studies have shown that pretreatment viremia and
hepatitis C virus—genotype are independent virus-related predictors for
the response to interferon- therapy: patients with lower pretreatment
viremia levels were shown to respond better to antiviral therapy than those
with higher levels of hepatitis C—virus RNA
[2,
3,
14]. Results of another study
showed that the total lymph node volume within the hepatoduodenal ligament is
smaller in patients with hepatitis C—virus RNA levels of less than
106 copies/ml than in those with higher viremia
[5]. In our study, we observed
that patients with a virologic response at the end of follow-up had a smaller
total perihepatic lymph node volume before treatment compared with
nonresponders. Therefore, the pretreatment total perihepatic lymph node volume
may be another predictive parameter for the antiviral response in patients
with chronic hepatitis C. As also shown in an earlier study
[5], no correlation was
observed between the size of perihepatic lymph nodes, hepatitis C virus
genotype, and liver function test results before treatment.
In conclusion, the data of the present study show that lymph nodes within the hepatoduodenal ligament can be detected by transabdominal sonography in patients with chronic hepatitis C and adequate visualization of the liver hilus before, during, and after treatment. The total perihepatic lymph node volume is increased in patients with chronic hepatitis C and changes in many patients according to the antiviral response leading to almost complete nonmalization in sustained virologic responders. The decrease in the perihepatic lymph node volume is associated with an improvement in liver histology. If confirmed in larger studies, sonographic evaluation of the hepatoduodenal ligament may replace the necessity of a liver biopsy after antiviral therapy.
Acknowledgments
We thank G. Herrmann (Department of Pathology, Johann Wolfgang Goethe
University Frankfurt au Main) for histologic examinations, H. Ackermann
(Department of Biostatistics, Johann Wolfgang Goethe-University Frankfurt au
Main) for statistical advice, and Sabine Dorn and Christine Hoffmann for
excellent support in managing our sonography department.
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