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Serum Hepatitis C Virus RNA Levels and Histologic Findings in Liver Allografts With Early Recurrent Hepatitis C.

Hepatitis C virus (HCV) infection is a common cause of end-stage liver disease requiring orthotopic liver transplantation (OLTx), and it is also the most frequent cause of chronic hepatitis in allografts.[1] Histopathologic features of chronic hepatitis C have been well described in immunocompetent patients,[2,3] and there are several reports on the pathology of hepatitis C in patients who underwent OLTx.[4-6] However, during the first few months after OLTx, histopathologic features of hepatitis C may be subtle or modified and therefore difficult to differentiate from other conditions, such as cellular rejection,[7] ischemia, drug-related injury, bile duct problems, sepsis, recurrence of original disease, and opportunistic infections that may involve liver allografts.

To determine the early histopathologic changes of recurrent hepatitis C and their relation with serum HCV RNA levels in patients who have undergone liver transplantation, we examined sequential liver biopsy specimens and quantified HCV RNA levels of corresponding plasma samples during the first 6 months following OLTx in patients undergoing transplantation for chronic HCV and cirrhosis.

MATERIALS AND METHODS

We studied 14 patients (6 men and 1 women; mean age, 54.6 years) who underwent OLTx for chronic HCV-associated cirrhosis at the Mount Sinai Hospital, New York, NY. The pre-OLTx serum samples of these patients were positive for anti-HCV when determined using a second-generation enzyme-linked immunoassay (Abbott Diagnostics, Chicago, Ill). The explanted livers showed chronic hepatitis and cirrhosis. We examined sequential liver biopsy specimens of these patients, which were obtained during the first 6 months after OLTx. There were 30 biopsy specimens: 9 were taken within the first 2 weeks, 9 between 2 and 6 weeks, 8 between 6 and 12 weeks, and 4 between 12 and 24 weeks following OLTx. The number of biopsy specimens varied from 1 to 5 per patient. We quantified the HCV RNA levels of 22 corresponding plasma samples using branched DNA signal amplification assay. The 22 plasma samples were collected within 2 weeks of the liver biopsy from all 14 patients, and the number of samples ranged from 1 to 4 per patient.

We also evaluated 25 liver biopsy specimens, which were chosen randomly from liver transplant recipients with chronic disease other than HCV infection as a control group. This group consisted of 9 liver allograft recipients (3 men and 6 women; mean age, 52.3 years), and the pathological diagnoses of the liver explants were alcoholic cirrhosis (3 cases), primary biliary cirrhosis (3 cases), primary sclerosing cholangitis (1 case), and autoimmune hepatitis (2 cases). They consisted of 7 biopsy specimens that were taken within the first 2 weeks, 10 that were taken between 2 and 6 weeks, 6 that were taken between 6 and 12 weeks, and 2 that were taken between 12 and 24 weeks after OLTx. The number of biopsy specimens varied from 1 to 4 per patient. The post-OLTx serum samples of these 25 cases were subjected to polymerase chain reaction (PCR), which was a more sensitive method for the detection of HCV RNA.

Histological Findings

Liver biopsies were performed for the diagnosis of allograft dysfunctions. The specimens were fixed in 10% neutral-buffered formalin, embedded in paraffin, sectioned at 5 [micro]m, and stained with hematoxylin-eosin. At least 3-level sections of each specimen were reviewed blindly without knowledge of the sequence of the time of biopsy or the clinical, serological, and branched DNA or PCR findings of HCV infection.

The following morphological lesions were semiquantitatively evaluated: lobular inflammation and focal necrosis (none, mild: involvement of less than one third of lobules, moderate: one third to two thirds of lobules, and severe: more than two thirds of lobules); the number of acidophilic bodies (none, mild: 1-2 per lobule, moderate: 3-5 per lobule, and severe: more than 5 per lobule); portal inflammation (none, mild: sprinkling of inflammatory cells in less than one third of portal tracts, moderate: increased inflammatory cells in one third to two thirds of portal tracts, and severe: dense packing of inflammatory cell in two thirds of portal tracts); piecemeal necrosis (none, mild: focal in rare portal tracts, moderate: less than 50% of the circumference of most portal tracts, and severe: more than 50% of the circumference of most portal tracts); and steatosis (none, mild: involvement of less than one third of lobules, moderate: one third to two thirds of lobules, and severe: more than two thirds of lobules). Histologic activity index (HAI) was assigned using the Knodell modified system (excluding fibrosis).[8,9] It combined scores of lobular inflammation and focal necrosis, piecemeal necrosis, and portal inflammation, which were graded as none (0), mild (1), moderate (3), and severe (4). The presence of bile duct damage, bile ductular proliferation, cholestasis, centrilobular coagulative necrosis, and bridging necrosis and the nature of the inflammatory cell infiltrate in the portal tracts were also reviewed. Fibrosis was defined as absent, portal, septal, transition to cirrhosis, and cirrhosis.

The diagnosis of cellular rejection was based on the presence of at least 2 of the following 3 findings: mixed portal inflammation including eosinophils, bile duct inflammation or damage, and inflammation of endothelial cells in the portal veins and central venules. When rejection was present, its severity was graded according to the National Institute of Diabetes and Digestive and Kidney Disease grading system.[10] Additionally, sections were evaluated with other histochemical or immunohistochemical techniques as necessary to exclude non-HCV hepatitis and infection, such as cytomegalovirus, Epstein-Barr virus, herpes simplex, and hepatitis B virus.

HCV RNA Quantitative Analysis

The Chiron HCV Assay is a signal-amplified oligonucleotide probe test for the specific detection and quantitative analysis of hepatitis C virus RNA in human serum. The 5' untranslated region and core genes of HCV RNA allow the RNA to be captured on the surface of a 96-microwell plate. Multiple copies of an alkaline phosphatase-linked probe and synthetic branched DNA molecules are hybridized to the immobilized complex. Viral detection is accomplished by incubation with a chemiluminescent substrate and by measuring the light emission generated by the bound alkaline phosphatase. The quantity of HCV RNA is calculated from a standard curve, and the lowest level of detection is 3.5 x [10.sup.5] Eq/mL.

HCV RNA Detection

The HCV RNA was isolated from 200 mL of serum using acid guanidinium thiocyanate-phenol-chloroform extraction method as previously described.[11] The purified RNA was resuspended in 100 [micro]L of TE buffer (10 mM Tris-HCl [pH 7.5], 0.1 mM EDTA). Reverse transcription PCR was performed by using a Gene Amp RNA PCR kit (Perkin Elmer, Norwalk, Conn). Reverse transcription and first PCR were performed in 100 [micro]L of mixture containing 50 mL of HCV RNA suspension, 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2 mM MgCl2, 0.2 mM dATP, 0.2 mM dGTP, 0.2 mM dTTP, 0.2 mM dCTP, 8 U of RNase inhibitor, 50 [micro]M MuLV reverse transcriptase, 2.5 U of Taq polymerase, 0.4 [micro]M outer primer pairs (sense, 5'-GCGACACTCCACCATAGAT-3', 2 to 20, and antisense, 5'-GCTCATGGTGCACGGTCTA-3', 312 to 330). The reverse transcription was carried out by incubation at 42 [degrees] C for 15 minutes, followed by inactivation of the reverse transcriptase by heating at 99 [degrees] C for 5 minutes and then cooling to 5 [degrees] C for 5 minutes. The reaction proceeded with the first PCR amplification using a 2-temperature protocol at 95 [degrees] C for 15 seconds and 60 [degrees] C for 30 seconds for 35 cycles in a thermocycler, GeneAmp PCR System 9600 (Perkin Elmer). The PCR reaction was completed by extension at 72 [degrees] C for 7 minutes. For the second PCR amplification, 5 mL of the PCR products from the first amplification were added to a 45-mL mixture containing the same components as the first PCR, except 0.2 [micro]M inner primer pairs (sense, 5'-CTGTGAGGAACTACTGTCT-3', 28 to 46, and antisense, 5'-ACTCGCAAGCACCCTATCA-3', 277-295). The same PCR protocol was used for the second PCR. A total of 20 [micro]L of the PCR products was examined by electrophoresis through a 2% agarose gel. The appearance of a band 268 base pairs long was considered a positive result.

Statistical Analysis

Statistical analysis was performed using the [chi square] test, Fisher exact test, Mann-Whitney U test, and linear regression test.

RESULTS

Histopathologic Features

The liver biopsy specimens of the HCV-positive and HCV-negative groups showed various degrees of lobular and portal changes, and the histopathologic features of both groups are summarized in Tables 1 and 2.
Table 1. Histopathologic Features of Liver Allografts(*)

 Lobular Acidophilic
 Inflammation Bodies Portal
 and Necrosis ([dagger]) Inflammation

 HCV+ HCV- HCV+ HCV- HCV+ HCV-

None 0 0 0 5 0 2
Mild 17 12 18 16 16 13
Moderate 12 10 12 4 13 8
Severe 1 2 0 0 1 2

 Piecemeal
 Necrosis
 ([double dagger]) Steatosis

 HCV+ HCV- HCV+ HCV-

None 21 24 16 16
Mild 4 1 13 5
Moderate 5 0 1 3
Severe 0 0 0 1


(*) HCV+ indicates HCV-positive group; HCV-, HCV-negative group.

([dagger]) P < .0127 between HCV+ and HCV- group determined by [chi square] test.

([double dagger]) P < .0369 between HCV+ and HCV- group determined by [chi square] test.
Table 2. Other Histopathologic Features in Liver Allografts(*)

 Lymphocyte
 Predominance Bile Duct Ductular
 ([dagger]) Damage Proliferation

 HCV+ HCV- HCV+ HCV- HCV+ HCV-

Present 15 6 18 13 25 22
Absent 15 19 12 12 5 3

 Cholestasis
 Necrosis Coagulative

 HCV+ HCV- HCV+ HCV-

Present 14 13 6 19
Absent 16 12 24 15


(*) HCV+ indicates HCV-positive group; HCV-, HCV-negative group.

([dagger]) P < .0958, determined by the Fisher exact test.

All biopsy specimens of the HCV-positive group showed mild-to-moderate numbers of acidophilic bodies, which were randomly scattered throughout the lobule (Figure 1). The earliest acidophilic bodies were found at 1 week after OLTx, such as acute hepatitis, and there was no portal fibrosis. The number of acidophilic bodies increased in sequential biopsy specimens of the HCV-positive group. The prevalence of acidophilic bodies, especially of moderate degree, was significantly higher in the HCV-positive group than HCV-negative group (P [is less than] .0127).

[Figure 1 ILLUSTRATION OMITTED]

Various degrees of lobular inflammation and focal necrosis characterized by sinusoidal lymphocytes and clustering of mononuclear inflammatory cells were observed in the HCV-positive group. However, there was no significant difference between the 2 groups. Other lobular features, such as steatosis and cholestasis, showed no statistically significant differences between the HCV-positive and HCV-negative groups. The lesions of coagulative necrosis were confined to zone 3 and were present in both groups.

Some HCV-positive biopsy specimens showed piecemeal necrosis, 4 with mild and 5 with moderate degree (Figure 2). The degree of piecemeal necrosis increased with time, and the earliest piecemeal necrosis of moderate degree was observed at 8 weeks after OLTx. One HCV-negative biopsy specimen had mild piecemeal necrosis. The presence and degree of piecemeal necrosis were significantly different between the 2 groups (P [is less than] .03689). In both groups, bridging necrosis was not seen up to the 6-month post-OLTx follow-up period.

[Figure 2 ILLUSTRATION OMITTED]

Mild-to-severe portal inflammation was seen in all HCV-positive biopsy specimens, and there was no significant difference between the 2 groups. The nature of the inflammatory cells in the portal tracts was also evaluated. Although they were of mixed cellularity to some extent, 15 biopsy specimens (50%) in the HCV-positive group showed mature lymphocyte predominance compared with only 6 biopsy specimens (24%) in the HCV-negative group (Figure 2). This finding was marginally significant (P [is less than] .0958). In the HCV-positive group, mature lymphocyte predominance became more obvious with time, sometimes forming lymphoid aggregates. However, there was no lymphoid follicle formation up to 6 months after OLTx. Other features in portal tracts, including bile duct damage and bile ductular proliferation, showed no significant differences between the 2 groups.

In the HCV-positive group, 6 biopsy specimens with portal fibrosis and 6 with septal fibrosis were present (Figure 3). The earliest septal fibrosis was observed at 1 month after OLTx, and the fibrosis progressed with time. Six HCV-negative biopsy specimens had portal fibrosis, but none had fibrous septa. The degree of fibrosis was significantly different between the HCV-positive and HCV-negative groups (P [is less than] .0266).

[Figure 3 ILLUSTRATION OMITTED]

The HAI scores showed no significant difference between the 2 groups but increased with time in the HCV-positive group 2 weeks after OLTx (P [is less than] .0344).

Concurrent cellular rejection was present in 20 biopsy specimens of the HCV-positive group; 12 were mild and 8 were moderate. In the HCV-negative group, there were 13 biopsy specimens with cellular rejection, 6 were mild, 3 moderate, and 4 severe (Figure 4). One biopsy specimen in the HCV-positive group showed cytomegalovirus hepatitis 12 weeks after OLTx, confirmed by immunohistochemical stain. There were no biopsy specimens with Epstein-Barr virus, herpes simplex, or hepatitis B virus in either group. Four biopsy specimens in the HCV-positive group and 3 in the HCV-negative group showed histological changes related to sepsis.[12] Mild nonspecific changes were seen in 2 biopsy specimens in the HCV-positive group and 6 in HCV-negative group.

[Figure 4 ILLUSTRATION OMITTED]

Post-OLTx HCV RNA Levels and Histologic Findings

The HCV RNA levels of 22 plasma samples were measured by branched DNA in which the time interval of liver biopsy and collection of plasma was less than 2 weeks. The HAI scores and HCV RNA levels of corresponding plasma samples are summarized in Table 3. The HAI showed no linear relationship to the HCV RNA levels. However, the biopsy specimens with high HAI scores tended to have higher HCV RNA levels (P [is less than] .0202). Other histopathologic features, which include steatosis, cholestasis, coagulative necrosis, bile duct damage, and ductular proliferation, showed no significant relation with post-OLTx HCV RNA levels.

Table 3. Hepatitis C Virus (HCV) RNA Levels and Modified Histologic Activity Index(*)
Histologic HCV RNA, Mean [+ or -] SE,
Activity Index Eq/mL x [10.sup.5]

1 - 3 (n = 8) 11.86 [+ or -] 4.174 (3.5 - 35.3)
4 - 9 (n = 14) 215.93 [+ or -] 65.981 (3.5 - 620.0)


(*) P < .0202, determined by Mann-Whitney U test.

Post-OLTx serum samples of all 25 patients who underwent transplantation for diseases other than HCV infection (control group) were negative for HCV RNA by reverse transcription PCR.

COMMENT

Nearly all patients undergoing OLTx for HCV have recurrent viremia, and the levels of HCV RNA continue to increase after OLTx (Figure 5), most likely due to the effect of immunosuppression on viral replication.[13,14] The histopathologic diagnosis of early recurrent hepatitis C is very important, especially during the first few months after OLTx, when immunosuppression is maximal and many other causes may contribute to liver allograft dysfunction, especially cellular rejection. In addition, there is evidence suggesting that increased immunosuppression given to patients with probable cellular rejection may exaggerate the hepatitis C.[15]

[Figure 5 ILLUSTRATION OMITTED]

In this study, the significantly different findings between the HCV-positive and HCV-negative groups were piecemeal necrosis, number of acidophilic bodies, and fibrous septum. These findings and the HAI scores increased significantly with time after OLTx and became more significant 8 weeks after OLTx. This is consistent with previous reports that recurrent hepatitis C can be diagnosed around 2 months after OLTx.[4,5]

The HAI scores in the first 2 weeks after OLTx in both groups were relatively high because of injury during OLTx, such as harvesting injury. The lymphocyte predominance in portal tracts was more frequent in the HCV-positive group and also increased with time after OLTx. Lymphoid follicle formation, one of the characteristic findings of hepatitis C,[2,3] however, was not observed during the 6-month post-OLTx follow-up in this study. This may be related to the immunosuppressive status and the relatively short follow-up period after OLTx.

Mild nonspecific, necroinflammatory lesions are often seen in earlier biopsy specimens of HCV-positive patients, and although retrospectively they may represent early features of recurrent hepatitis C, similar features were also observed in the HCV-negative group in which HCV cannot be incriminated. Serial biopsy specimens, therefore, are important for a definite diagnosis of recurrent hepatitis C.[6]

The pathogenesis of hepatitis C is not clear. However, HCV may induce hepatocellular damage by both immune-mediated mechanisms and/or direct cytopathicity.[16,17] Several studies in immunocompetent patients have demonstrated that serum HCV RNA levels tended to increase with the progression of histopathologic changes of the liver and correlated with the lobular inflammation,[18-21] and a higher HCV RNA titer in liver allografts has been associated with more severe liver damage.[22,23] These findings suggest that increased viral replication plays a role in liver injury and progression of liver disease and favor a direct cytopathic mechanism of HCV.

In other studies, however, high HCV RNA levels were seen in the absence of hepatitis or with only mild damage in liver allografts,[24-26] suggestive of an immune-mediated mechanism. In this study, the biopsy specimens with higher HAI scores tended to have higher serum HCV RNA levels; however, HCV RNA levels were scattered, and there was no linear relation between them. This finding suggests that both cytopathic and immune-mediated mechanisms may be involved in the pathogenesis of hepatitis C. Other factors, such as genotype of HCV, especially type 1b, may influence the status of HCV replication and its relation to liver damage.[27,28]

In conclusion, liver biopsy specimens are helpful for the diagnosis or confirmation of early recurrent HCV infection in liver allografts, and the significant findings are acidophilic bodies, especially moderate numbers, piecemeal necrosis, lymphocyte predominance in the portal tracts, and fibrous septum formation. These lesions and the HAI scores increased with time after OLTx; therefore, serial liver biopsy specimens are required for a definite diagnosis. The HCV RNA levels are usually higher in patients who display signs of more severe liver damage; however, linear correlation in this limited number of samples was not found.

References

[1.] Read AE, Donegan E, Lake J, et al. Hepatitis C in patients undergoing liver transplantation. Ann Intern Med. 1991;114:282-284.

[2.] Scheuer P, Ashrafzadeh P, Sherlock S, Brown D, Dusheiko G. The pathology of hepatitis C. Hepatology. 1992;15:567-571.

[3.] Bach N, Thung SN, Schaffner F. The histological features of chronic hepatitis C and autoimmune hepatitis: a comparative analysis. Hepatology. 1992;15:572-577.

[4.] Ferrell LD, Wright TL, Roberts J, Ascher N, Lake J. Hepatitis C viral infection in liver transplant recipients. Hepatology. 1992;16:865-876.

[5.] Thung SN, Shim KS, Shieh YSC, et al. Hepatitis C virus in liver allografts. Arch Pathol Lab Med. 1993;117:145-149.

[6.] Petrovic LM, Villamil FG, Viering JM, Makowka L, Geller SA. Comparison of histopathology in acute allograft rejection and recurrent hepatitis C infection after liver transplantation. Liver Transplant Surg. 1997;3:398-406

[7.] Guido M, Thung SN. Distinguishing rejection from recurrent viral hepatitis on liver biopsy. Viral Hepatitis Rev. 1998;4:127-136.

[8.] Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1:431-435.

[9.] Hytiroglou P, Thung SN, Gerber MA. Histological classification and quantitation of the severity of chronic hepatitis: keep it simple! Semin Liver Dis. 1995; 15:414-421.

[10.] Demetris AJ, Seaberg EC, Batts KP, et al. Reliability and predictive value of the National Institute of Diabetes and Digestive and Kidney Disease Liver Transplantation database nomenclature and grading system for cellular rejection of liver allografts. Hepatology. 1995;21:408-416.

[11.] Chomczynski P, Sacchi N. Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987; 162:156-159.

[12.] Lefkowitch JH. Bile ductular cholestasis: an ominous histopathologic sign related to sepsis and "cholangitis lenta." Hum Pathol. 1982;13:19-24.

[13.] Feray C, Gigou M, Samuel D, et al. The course of hepatitis C virus infection after liver transplantation. Hepatology. 1994;20:1137-1143.

[14.] Poterucha J, Gross JB. Hepatitis C after liver transplantation. Gastroenterology. 1995;108:1314-1317.

[15.] Sheiner PA, Schwartz ME, Mor E, et al. Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation. Hepatology. 1995;21:30-34.

[16.] Gonzales-Peralta R, Davis GL, Lau JYN. Pathogenetic mechanisms of hepatocellular damage in chronic hepatitis C virus infection. J Hepatol. 1994;21: 255-259.

[17.] Gonzales-Peralta RP, Lau JYN. Pathogenesis of hepatocellular damage in chronic hepatitis C virus infection. Semin Gastrointest Dis. 1995;6:28-34.

[18.] Lau JYN, Davis GL, Kniffen J, et al. Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet. 1993;341:1501-1504.

[19.] Hagiwara H, Hayashi N, Mita E, et al. Quantitation of hepatitis C virus RNA in serum of asymptomatic blood donors and patients with type C chronic liver disease. Hepatology. 1993;17:545-550.

[20.] Kato N, Yokosuka O, Hosoda K, Ito Y, Ohto M, Omata M. Quantification of hepatitis C virus by competitive reverse transcription-polymerase chain reaction: incidence of the virus in advanced liver disease. Hepatology. 1993;18:1620.

[21.] Gretch D, Corey L, Wilson J, et al. Assessment of hepatitis C virus RNA levels by quantitative competitive RNA polymerase chain reaction: high-titer viremia correlates with advanced stage of disease. J Infect Dis. 1994;169:1219-1225.

[22.] Gretch DR, Bacchi CE, Corey L, et al. Persistent hepatitis C virus infection after liver transplantation: clinical and virological features. Hepatology. 1995;22: 1-9.

[23.] Gane EJ, Naoumov NV, Qian K-P, et al. A longitudinal analysis of hepatitis C virus replication following liver transplantation. Gastroenterology. 1996;110: 167-177.

[24.] Chazouilleres O, Kim M, Combs C, et al. Quantitation of hepatitis C virus RNA in liver transplant recipients. Gastroenterology. 1994;106:994-999.

[25.] Wright TL, Donegan E, Hsu HH, et al. Recurrent and acquired hepatitis C viral infection in liver transplant recipients. Gastroenterology. 1992;103:317-322.

[26.] Asanza C, Garcia-Monzon C, Clemente G, et al. Immunohistochemical evidence of immunopathogenetic mechanisms in chronic hepatitis C recurrence after liver transplantation. Hepatology. 1997;26:755-763.

[27.] Feray C, Gigou M, Samuel D, et al. Influence of the genotypes of hepatitis C virus on the severity of recurrent liver disease after liver transplantation. Gastroenterology. 1995;108:1088-1096.

[28.] Pageaux GP, Ducos J, Mondain A-M, et al. Hepatitis C virus genotypes and quantitation of serum hepatitis C virus in liver transplant recipients: relationship with severity of histological recurrence and implication in the pathogenesis of HCV infection. Liver Transplant Surg. 1997;3:501-505.

Accepted for publication May 10, 2000.

From the Department of Pathology, Yonsei University, College of Medicine, Seoul, Korea (Dr Park); and The Lillian and Henry M. Stratton--Hans Popper Department of Pathology (Drs Zhang and Thung), and Recanati-Miller Transplant Institute, Department of Surgery (Drs Boros, Sheiner, and Kim-Schluger), The Mount Sinai School of Medicine, New York, NY.

This study was supported partially by research fund from the Institute of Gastroenterology of Yonsei University.

Reprints: Swan N. Thung, MD, Department of Pathology, PO Box 1194, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029 (e-mail: swan_thung@smtplink.mssm.edu).
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Author:Park, Young Nyun; Boros, Peter; Zhang, David Y.; Sheiner, Patricia; Kim-Schluger, Leona; Thung, Swan
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:9SOUT
Date:Nov 1, 2000
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