SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES

Key Concepts:

  • 1
    Early recurrence of hepatitis C is universal.
  • 2
    Typical histopathologic features of hepatitis C virus (HCV) and acute allograft rejection (AAR) exist.
  • 3
    Early recurrent HCV may be differentiated from AAR.
  • 4
    Liver biopsy plays a role in diagnosing HCV and AAR.
  • 5
    Risk factors for recurrent HCV should be known.
  • 6
    The natural history of recurrent HCV should be known.
  • 7
    The future role of ancillary studies beyond liver biopsy is assessed. Liver Transpl 12:S32–S37, 2006. © 2006 AASLD.

End-stage liver disease associated with hepatitis C virus (HCV) infection has become the leading indication for liver transplantation (LT) worldwide. The HCV recurrence, however, is universal, and recurrent viral infection is now the most frequent cause of morbidity in the posttransplant setting.1–4 It has been well documented that HCV RNA can be detected in the peripheral blood within a few days after transplantation, often reaching the titers much higher than the pretransplantation levels.5, 6 Histopathologic features of recurrent HCV infection, although perhaps initially very subtle, may become evident within the first week after LT. Liver biopsy, despite sometimes inconclusive and ambiguous findings, remains the gold standard for the assessment and evaluation of recurrent HCV-associated hepatitis.7, 8 The severity of the recurrent viral hepatitis and the disease progression are highly variable. Currently there is no single marker or combination of variables predictive of progression.2, 9, 10

The natural history of recurrent HCV hepatitis is not as benign and indolent as earlier studies have suggested. It has been shown that the progression of recurrent HCV infection has an accelerated course, leading to cirrhosis in 20% of the patients within 5 years, and as many as 50% within the 10 years after LT.2, 11, 12 A number of factors, including virus, host, donor age, and modalities of treatment, may contribute to the severity and the progression of the disease.2 Antiviral therapy—the combination of interferon alfa and ribavirin in particular—is beneficial in approximately 15–20% of patients with recurrent HCV infection. Approximately 10% of patients with recurrent HCV hepatitis who progress to cirrhosis ultimately develop a graft failure and require retransplantation.2, 12–15

Both acute allograft rejection (AAR) and recurrent HCV infection may present with similar clinical findings, including elevated serum transaminases, elevated bilirubin, and alkaline phosphatase. Differentiating the early onset of the recurrent HCV infection from AAR remains one of the most challenging issues in the posttransplantation setting. Identifying the subset of patients with early onset of recurrent HCV has a marked impact on further management of already immunosuppressed patients. Both conditions can be, and often are, modified by immunosuppressive therapy, confounding the already complex relationship between recurrent HCV and rejection, and it is not surprising that early HCV recurrence can be difficult to differentiate from AAR clinically and histologically.7, 8, 16

TYPICAL HISTOPATHOLOGIC FEATURES OF AAR

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES

Typical histopathologic features of AAR are easily recognized and include (1) mixed inflammatory infiltrate with a variable number of eosinophils, (2) bile duct injury with infiltrating lymphocytes, and (3) endothelialis (endotheliitis).

The inflammatory infiltrate associated with AAR is typically described as mixed, and it is composed of a mixture of lymphocytes, lymphoblasts, a variable number of eosinophils, histiocytes, and sometimes neutrophils. The inflammatory infiltrate is generally centered around the bile ducts. Lymphoid aggregates are usually not associated with AAR. The degree of bile duct injury is variable, but the important aspect of AAR-associated bile duct injury is the presence of infiltrating lymphocytes in the bile duct epithelium, often associated with degenerative changes of the biliary epithelium and with true epithelial necrosis (Fig. 1).

thumbnail image

Figure 1. AAR. Mixed inflammatory infiltrate, increased number of eosinophils, and bile duct injury (hematoxylin and eosin, original magnification, 200×).

Download figure to PowerPoint

Endothelialitis is considered a hallmark of AAR and often is seen in both portal and central veins. In severe cases, the arterial endothelium can also be affected.

TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES

Typical histopathologic features of HCV infection in the nontransplantation setting are easily recognized and usually are not a diagnostic problem for a pathologist. The spectrum of findings include chronic inflammatory infiltrate within the portal tracts composed predominantly of lymphocytes, often in the form of lymphoid aggregates. There is usually a relatively mild and focal periportal inflammation and interface hepatitis. A mild to moderate degree of lobular inflammation and liver cell necrosis are usually present, as well as a variable degree of steatosis7, 8, 16 (Fig. 2).

thumbnail image

Figure 2. Recurrent HCV hepatitis. Portal inflammatory infiltrate and focal interface hepatitis. Note that bile duct is not involved with inflammatory changes (hematoxylin and eosin, original magnification, 200×).

Download figure to PowerPoint

The patients with recurrent HCV infection can be arbitrarily divided into at least 4 groups on the basis of whether and when they develop clinically and histologically manifested hepatitis. These groups are as follows: (1) no hepatitis (HCV viremia, asymptomatic); (2) early, <3 months after LT; (3) 3–6 months after LT; and (4) >6–12 months after LT.

Histopathologic features of early recurrent HCV infection—<3 months after LT—may be subtle and may include the following:

  • Sinusoidal dilatation.

  • Lobular inflammation (mild).

  • Portal tract inflammation (mild).

  • Focal, mild steatosis.

  • Kupffer cell hyperplasia.

  • Overlap features of HCV and AAR (Figs. 3 and 4).

thumbnail image

Figure 3. Mild acute rejection. Inflammatory infiltrate is relatively mild, but in addition to lymphocytes, eosinophils are present. Mild bile duct injury is also present (hematoxylin and eosin, original magnification, 200×).

Download figure to PowerPoint

thumbnail image

Figure 4. Liver biopsy from patient with overlapping features of acute rejection and recurrent HCV hepatitis. Shown here are lobular inflammation and liver cell necrosis (hematoxylin and eosin, original magnification, 200×).

Download figure to PowerPoint

Although the findings may vary, the earliest features associated with early HCV recurrence include the sinusoidal dilatation, lobular inflammation, and focal apoptotic liver cell necrosis, sometimes associated with variable degrees of steatosis. Portal inflammation is initially relatively mild. As the disease progresses, there is more portal inflammation, usually with mild focal interface hepatitis. The inflammatory infiltrate is predominantly mononuclear and often forms lymphoid aggregates.7

With time, recurrent HCV infection is histologically indistinguishable from HCV-associated hepatitis in the nontransplant setting. There may be a relatively mild bile duct injury, including nuclear overlapping and epithelial vacuolization, but usually the degree of bile duct injury is not such as that seen in AAR (Table 1).

  • Several points should be kept in mind when assessing recurrent HCV infection:

  • Spectrum of histopathologic changes during early recurrence.

  • Recurrent disease is more aggressive and more progressive disease.

  • Atypical histologic patterns of HCV recurrence.

  • Overlap features of HCV and AAR.

Table 1. Differentiating Early Recurrent HCV (<3 Months After Liver Transplantation) from AAR Liver Biopsy Findings
CharacteristicAAREarly HCV
  1. Abbreviations: AAR, acute allograft rejection; HCV, hepatitis C virus.

Portal tract/inflammationMixed (variable number of eosinophils)Mononuclear
Bile duct injuryPresent, prominentNo/minimal
EndothelialitisPresentAbsent
Sinusoidal dilatationAbsentPresent
Parenchymal changesMildPresent
 Inflammation/liver cell necrosisMinimal/mildPresent
 SteatosisAbsentPresent
 CholestasisPresentMay be present
FibrosisAbsentAbsent

GRADING AND STAGING OF RECURRENT HCV

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES

The inflammation and liver cell necrosis associated with recurrent HCV infection should be graded according to any of the widely used and accepted grading criteria, similarly to the biopsy samples with HCV in the nontransplant setting. Conversely, if the changes of AAR are present, the rejection should be graded by the Banff criteria.17

In those cases where the overlapping features of both recurrent HCV and AAR are present, the grading of either of the conditions may not be helpful. Follow-up and sometimes serial liver biopsies may be necessary in order to establish the diagnosis.

ATYPICAL HISTOLOGIC PATTERNS

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES

Atypical histologic patterns associated with HCV recurrence include ballooning, cholestatic features, HCV fibrosing cholestatic hepatitis (FCH) variant, and severe bile duct injury. For late HCV recurrence (>6–12 months after LT), the following features should be assessed: chronic hepatitis, fibrosis/cirrhosis, FCH, nodular regenerative hyperplasia, and increased incidence of ductopenia or ductopenic rejection.

ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES

The following play a key role in the diagnosis and management of HCV infection in the liver allograft: early changes of recurrent disease; grading and staging of HCV; assessment of the response to treatment (immunosuppressive or antiviral therapy); serial biopsy; assessment of the progression of the disease's natural history; and exclusion of any other conditions.

RISK FACTORS FOR RECURRENT HCV INFECTION

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES

Although recurrent HCV infection is universal, the timing and the severity of the disease is highly variable. Several studies have identified a number of potential risk factors for recurrent HCV infection, and they include the viral HCV-related factors (virus load, genotype, quasispecies) as well as coinfection with other viruses such as cytomegalovirus, HHV-6, hepatitis B virus, and hepatitis D virus.2, 13, 18 It has been shown that the donor-related factors play an important role, including the organ cold/warm ischemia-induced preservation injury, which is associated with earlier recurrence and poorer survival outcomes than non-HCV transplant patients.19 The other factors include, but are not limited to, immunosuppression in general, but also the episodes of acute rejection and additional pulses of corticosteroids and basiliximab and muromonab (OKT3) treatment.12, 20 A recent study provides evidence that DRB1 donor-recipient mismatch affects both the occurrence and the progression of recurrent HCV hepatitis.21

Cholestasis and the FCH variant of recurrent HCV have both been associated with more severe and more rapidly progressive disease.8, 9 There are still no well-defined features that would predict which patients will develop recurrent HCV hepatitis and those who will not.

NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES

Although the natural history of posttransplantation recurrent HCV hepatitis is variable, it has become evident that the recurrent HCV hepatitis has not only become a more progressive disease, but also that the progression occurs more quickly in the recent years compared to the patients who underwent LT in the early 1990.2 Risk factors that have been associated with more aggressive HCV recurrence include treated AAR, cytomegalovirus infection, and use of OKT3.2, 13 It appears that the overall immunosuppression effect is more important than a single immunosuppressive agent.

The results from 2 transplant centers provided a model identifying at least 5 predictive risk factors for progression to severe recurrent disease within 2 years: donor age (>50 years old), HCV genotype 1b, use of OKT3, induction with mycophenolate mofetil, and brief prednisone and azathioprine use. However, this model is not sensitive enough to predict outcome in an individual patient.2

The histologic activity of recurrent hepatitis C was found predictive in some studies, and by applying Ishak's scoring system, the histological activity index of 9 was 100% sensitive and specific in identifying those patients who developed cirrhosis within the mean follow-up of 38 months.22 One study recently demonstrated that an increased activation of stellate cells in the early posttransplantation period (<4 months) help identify patients who are at increased risk for developing extensive fibrosis within 2 years of LT.23

It is less clear whether the natural course of and progression of recurrent HCV infection is significantly different in patients undergoing living donor liver transplantation compared with those receiving deceased donor liver. One study showed that during the mean follow-up of 40 months, there was no significant difference in patient or graft survival or the percentage of patients who developed acute rejection after living donor liver transplantation. The degree of inflammation increased stepwise over 3 years but was not markedly different in the 2 groups. The mean fibrosis score and the percentage of patients with fibrosis increased stepwise after deceased donor liver transplantation, but appeared to plateau 12 months later.24

The Extended Criteria Donor has been used in the last several years in the era of organ donor shortage. Limited data, however, are available regarding how the selection of such donors affects the survival of the graft and patients. Preliminary results from one transplant center have shown that that the incidence of severe HCV recurrence was significantly higher in this group (2-year follow-up).

LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES

Immunohistochemistry, In Situ Hybridization, and Polymerase Chain Reaction

The liver biopsy will continue to play an important role in the assessment of the histopathologic changes after LT. In addition to further refining the histopathologic criteria that may help establish the diagnosis of recurrent HCV and differentiate early recurrent HCV from AAR, there are several areas that may be helpful in achieving those goals.

Although specific anti-HCV antibodies have not been very reliable in detecting the tissue expression of HCV-associated antigens, several studies have shown that there is a correlation between the tissue expression of HCV antigens, high titers of serum HCV RNA, and early histopathologic changes of recurrent HCV hepatitis.25–27 It has been recently reported that C4d, as a marker of the activated complement cascade, is expressed in AAR with a specificity of 90%.28

In situ hybridization is another helpful method that is not used routinely, but coupled with biopsy findings, it may be helpful in the overall assessment of disease activity. It is usually known that the patient has recurrent HCV infection, reflected in HCV RNA positivity (polymerase chain reaction in the serum and tissue); however, it is important to assess the type and the degree of injury affecting the liver parenchyma.27 AAR and chronic rejection have been associated with relatively low serum HCV RNA, in contrast to recurrent HCV and its variant FCH in particular.15

DR Antigens

HLA class II antigens have been documented to be associated with more severe chronic HCV infection in the nontransplant setting. Because host immunogenicity is crucial in the natural course and the progression of HCV infection, identification of the recipient DR antigens and the level of DR mismatching (between the donor and the recipient) may help in assessing the relative risk of more severe HCV recurrence and allograft outcome after LT. It has been shown that the HCV-positive recipients with DR3 antigens had reduced allograft survival, higher rate of HCV recurrence, and more severe liver disease.30

Gene Rearrangement

Several recent studies have shown that AAR and recurrent HCV are associated with distinct mRNA patterns, and in one study, recurrent HCV was associated with the overexpression of 25 genes. Conversely, 15 genes were underexpressed in AAR. Furthermore, AAR was associated with the relative overexpression of genes associated with major histocompatibility complex 1 and 2, insulinlike growth factor 1, apoptosis induction, and T cell activation.30 These findings suggest that the differential mRNA expression and their products, such as immunomodulatory peptides, may be useful in further distinguishing between AAR and recurrent HCV.31

Cytokine Gene Polymorphism

Cytokines play an important role in the immune response to viral infection, where the type 1 immune response (associated with interferon gamma and interleukin 12) has direct antiviral effect and is critical for virus clearance. Th1 interferons also help perpetuate chronic inflammatory response to persistent viral infection. It has been shown that the gene polymorphism of the tumor growth factor beta 1 gene (genetic ability to produce high levels of tumor growth factor beta 1) correlates with its in situ expression in patients with recurrent HCV and also correlates with the degree of fibrosis after LT. In contrast, the interferon gamma polymorphism (genetic ability to produce low levels of interferon gamma), but not tumor growth factor beta gene polymorphism, correlates with early recurrent HCV hepatitis after transplantation.32

These findings might help identify subsets of patients who are at risk of developing early recurrent HCV infection.

Role of Chemokines

Chemokines have many different functions, but the most important is the recruitment of the subsets of inflammatory cells to specific sites of tissue injury and inflammation—in the case of HCV infection, to the liver parenchyma. Both chemokines and their receptors play a critical role in leukocyte recruitment, activation, and differentiation. Two chemokine receptors in particular, CXCR3 and CCR5 (Th1-associated), are present in T cells from HCV-infected patients. The outcome of HCV infection depends on the patient's immune response. It appears that a vigorous immune response, primarily Th1 cell mediated, is necessary for virus clearance. When the elimination of the HCV fails, the patient develops chronic hepatitis. The chemokine receptors CXCR3 and CXCR5 and the ligands for CXCR3 (IP-10, ITAC, and Mig), all of which are interferon-inducible proteins, are increased in the liver of HCV-infected patients in the nontransplant setting.33–35 A complex interplay between the effector immune cells, cytokines, and subsets of chemokines plays a role in recruiting inflammatory cells to the liver, promoting inflammation and fibrogenesis in chronic HCV-associated hepatitis.

Limited information, however, is available about their role in the liver in the posttransplantation setting. Several studies have shown the importance of the CXCR3 chemokine system in renal allografts with an increased expression of IP-10, which further leads to activation of CXCR3 and CCR5, directing T cells to the renal allograft and mediating allograft rejection.36 Preliminary data have also shown that there is an increased expression of CXCR3 in AAR in liver allograft biopsy samples compared with recurrent HCV, indicating that that the interferon-producing T cells play a role in allograft rejection.

REFERENCES

  1. Top of page
  2. Abstract
  3. TYPICAL HISTOPATHOLOGIC FEATURES OF AAR
  4. TYPICAL HISTOPATHOLOGIC FEATURES OF HCV INFECTION
  5. GRADING AND STAGING OF RECURRENT HCV
  6. ATYPICAL HISTOLOGIC PATTERNS
  7. ROLE OF LIVER BIOPSY IN RECURRENT HCV INFECTION
  8. RISK FACTORS FOR RECURRENT HCV INFECTION
  9. NATURAL HISTORY AND PROGRESSION OF RECURRENT HCV INFECTION
  10. LIVER BIOPSY AND BEYOND: FUTURE ROLE OF ANCILLARY STUDIES
  11. REFERENCES
  • 1
    Brown RS. Hepatitis C and liver transplantation. Nature. 2005; 436: 973978.
  • 2
    Berenguer M, Crippin J, Gish R, Bass N, Bostrom A, Netto G, et al. A model to predict severe HCV-related disease following liver transplantation. Hepatology. 2003: 38: 3441.
  • 3
    Feray C, Gigou M, Samuel D, Paradis V, Wilber J, David MF, et al. The course of hepatitis C virus infection after liver transplantation. Hepatology. 1994; 29: 11371143.
  • 4
    Sallie R, Cohen AT, Tibbs CJ, Portmann BC, Rayner A, O'Grady JG, et al. Recurrence of hepatitis C following orthotopic liver transplantation: a polymerase chain reaction and histological study. J Hepatol. 1994; 21: 536542.
  • 5
    Aardema KL, Nakhleh RE, Terry LK, Burd EM, Ma CK, Moonka DK, et al. Tissue quantification of hepatitis C virus RNA with morphologic correlation in the diagnosis of recurrent hepatitis C virus in human liver transplants. Mod Pathol. 1999; 12: 10431049.
  • 6
    Park YN, Boros P, Zhang DY, Sheiner P, Kim-Schluger L, Thung SN. Serum hepatitis C virus RNA levels and histologic findings in liver allografts with early recurrent hepatitis C. Arch Pathol Lab Med. 2000; 124: 16231627.
  • 7
    Petrovic LM, Villamil FG, Vierling JM, Makowka L, Gellar SA. Comparison of histopathology in acute allograft rejection and recurrent hepatitis C infection after liver transplantation. Liver Transpl Surg. 1997; 3: 398406.
    Direct Link:
  • 8
    Sreekumar R, Gonzales-Koch A, Maor-Kendler Y, Batts K, Moreno-Luna L, Poterucha J, et al. Early identification of recipients with progressive histologic recurrence of hepatitis C after liver transplantation. Hepatology. 2000; 32: 11251130.
  • 9
    Greenson JK, Svoboda-Newman SM, Merion RM, Frank TS. Histologic progression of recurrent hepatitis C in liver transplant allografts. Am J Surg Pathol. 1996; 20: 731738.
  • 10
    Gane EJ, Naoumov NV, Qian KP, Mondelli M, Maertens G, Portmann BC, et al. A longitudinal analysis of hepatitis C virus replication after liver transplantation. Gastroenterology. 1996; 110: 167177.
  • 11
    Berenguer M, Ferrell L, Watson J, Prieto M, Kim M, Rayon M, et al. HCV-related fibrosis progression following liver transplantation: Increase in recent years. J Hepatol. 2000; 32: 673684.
  • 12
    Rosen HR, Shackleton CR, Higa L, Gralnek IM, Farmer DA, McDiarmid SV, et al. Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation. Am J Gastroenterol. 1997; 92: 14531457.
  • 13
    Sugo H, Balderson GA, Crawford DH, Fawcett J, Lynch SV, Strong RW, et al. The influence of viral genotypes and rejection episodes on the recurrence of hepatitis C after liver transplantation. Surg Today. 2003; 33: 421425.
  • 14
    Stravitz RT, Shiffman ML, Sanyal AJ, Luketic VA, Sterling RK, Heuman DM, et al. Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation. Liver Transpl. 2004; 10: 850858.
  • 15
    Demetris AJ, Eghtesad B, Marcos A, Ruppert K, Nalesnik MA, Randhawa P, et al. Recurrent hepatitis C in liver allografts: prospective assessment of diagnostic accuracy, identification of pitfalls, and observations about pathogenesis. Am J Surg Pathol. 2004; 28: 658669.
  • 16
    Baiocchi L, Tisone G, Palmieri G, Rapicetta M, Pisani F, Orlando G, et al. Hepatic steatosis: a specific sign of hepatitis C reinfection after liver transplantation. Liver Transpl Surg. 1998; 4: 441447.
  • 17
    Banff schema for grading liver allograft rejection: an international consensus document. Hepatology. 1997; 25: 658663.
  • 18
    Prieto M, Berenguer M, Rayon JM, Cordoba J, Arguello L, Carrasco D, et al. High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes. Hepatology. 1999; 29: 250256.
  • 19
    Watt KD, Lyden ER, Gulizia JM, McCashland TM. Recurrent hepatitis C posttransplant: early preservation injury may predict poor outcome. Liver Transpl. 2006; 12: 134139.
  • 20
    Taggart RA, Terrault NA, Vardanian AJ, Bostrom A, Feng S. Hepatitis C etiology of liver disease is strongly associated with early acute rejection following liver transplantation. Liver Transpl. 2004; 10: 975985.
  • 21
    Belli LS, Burra P, Poli F, Battista Alberti A, Silini E, Zavaglia C, et al. HLA-DRB1 donor-recipient mismatch affects the outcome of hepatitis C disease recurrence after liver transplantation. Gastroenterology. 2006; 130: 695702.
  • 22
    Guido M, Fagiuoli S, Tessari G, Burra P, Leandro G, Boccagni P, et al. Histology predicts cirrhotic evolution of post-transplant hepatitis C. Gut. 2002; 50: 697700.
  • 23
    Russo MW, Firpi RJ, Nelson DR, Schoonhoven R, Shrestha R, Fried MW. Early hepatic stellate cell activation is associated with advanced fibrosis after liver transplantation in recipients with hepatitis C. Liver Transpl. 2005; 11: 12351241.
  • 24
    Shiffman ML, Stravitz RT, Contos MJ, Mills AS, Sterling RK, Luketic VA, et al. Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation. Liver Transpl. 2004; 10: 12481255.
  • 25
    Vargas V, Krawcynski K, Castells L, Martinez N, Esteban J, Allende H, et al. Recurrent hepatitis C virus infection after liver transplantation: immunohistochemical assessment of the viral antigens. Liver Transpl Surg. 1998; 4: 320327.
  • 26
    Nuovo GJ, Holly A, Wakely P Jr, Frankel W. Correlation of histology, viral load, and in situ viral detection in hepatic biopsies from patients with liver transplantation secondary to hepatitis C infection. Hum Pathol. 2002; 33: 277284.
  • 27
    Fenwick F, Bassendine MF, Agarwal K, Bevitt D, Pumeechockchai W, Burt AD, et al. Immunohistochemical assessment of hepatitis C virus antigen in cholestatic hepatitis after liver transplantation. J Clin Pathol. 2006; 59: 174178.
  • 28
    Schmeding M, Dankof A, Krenn V, Krukemeyer MG, Koch M, Spinelli A, et al. C4d in acute rejection after liver transplantation—a valuable tool in differential diagnosis to hepatitis C recurrence. Am J Transpl. 2006; 6: 523530.
  • 29
    Kimball P, Stravitz T. DR antigens influence graft outcome and HCV recurrence after liver transplantation. Transpl Proc. 2005; 37: 10991100.
  • 30
    Sreekumar R, Rasmussen DL, Wiesner RH, Charlton MR. Differential allograft gene expression in acute cellular rejection and recurrence of hepatitis C after liver transplantation. Liver Transpl. 2002; 8: 1421.
  • 31
    Smith MW, Walters KA, Korth MJ, Fitzgibbon M, Proll S, Thompson JC, et al. Gene expression patterns that correlate with hepatitis C and progression to fibrosis in liver transplant recipients. Gastroenterology. 2006; 130: 179181.
  • 32
    Ben-Ari Z, Pappo O, Druzd T, Sulkes J, Klein T, Samra Z, et al. Role of cytokine gene polymorphism and hepatic transforming growth factor beta1 expression in recurrent hepatitis C after liver transplantation. Cytokine. 2004; 27: 714.
  • 33
    Heydemann M, Shields P, McCaughan G, Adams D. Cytokines and chemokines in the immune response to hepatitis C infection. Curr Opin Infect Dis. 2001; 14: 279287.
  • 34
    Charo IF, Ransohoff R. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med. 2006; 354: 610621.
  • 35
    Zeremski M, Petrovic LM, Talal AH. Chemokines as inflammatory mediators in chronic hepatitis C virus infection. Hepatology. In press.
  • 36
    Akashi S, Sho M, Kashizuka H, Hamada K, Ikeda N, Kuzumoto Y, et al. A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection. Transplantation. 2005; 80: 378384.