Cirrhosis and Liver Transplantation: New Perspectives

## **Chapter 9**

## New Perspectives on the Use of Sub-Optimal Donor Livers

*Maria Eugenia Cornide-Petronio, Mariana Mendes-Braz, Mónica B. Jiménez-Castro, Jordi Gracia-Sancho and Carmen Peralta*

### **Abstract**

Liver transplantation is the therapy of choice for patients with end-stage liver disease. However, a shortage of donor organs remains a major obstacle to the widespread application of liver transplantation. To overcome this problem, transplant centers have developed strategies to expand the organ donor pool, including the routine use of sub-optimal donor livers. However, these have an increased risk of initial poor function or primary non-function that may cause greater risk of morbidity in the recipient. This chapter aims to describe the pathophysiological changes that may occur in sub-optimal donor livers, focusing on viral infections, since, after transplantation, infection of the graft is almost universal and can lead to chronic hepatitis, cirrhosis, and graft failure. The different experimental models as well as the clinical outcomes of the transplantation of sub-optimal donor livers with viral infections will be discussed. Such information may be useful to guide the design of better experimental models than those described to date as well as the effective use of sub-optimal livers with successful clinical application.

**Keywords:** liver transplantation, fibrosis, HCV, HBC, treatment

#### **1. Introduction**

End-stage liver disease is associated with high morbidity and mortality, and the only cure is orthotopic liver transplantation (LT). The number of people awaiting LT continues to increase [1] and exceeds the number of available grafts. Between 20 and 30% of patients waiting for LT will die on the waiting list or are delisted because of disease progression [2]. The large imbalance between the growing pool of potential LT recipients and the scarcity of donor organs has led to efforts to maximize the number of existing donors and identify possible new donors based on the use of liver grafts that are currently considered unsuitable for transplant due to their pathological condition [3]. To expand the potential donor pool, the clinical and scientific community is continually modifying the criteria for an acceptable liver donor and is turning to marginal or extended-criteria donors to meet waiting list demands [4]. Thus organs infected with hepatitis B (HBV) or C virus (HCV) are increasingly being used [5], although the risk to recipients of using such grafts remains unclear [6].

Over 2 billion people across the world have serological evidence of present or past infection with HBV and more than 350 million individuals are estimated to be chronically infected [7]. It is estimated that 2–15% of liver donors are anti-hepatitis B core antigen (anti-HBc) positive. The proportion of positive anti-HBc livers in donors aged 60 years or over may rise to as much as 25% [8, 9]. Acquisition of HBV remains a concern after LT because the majority of infections occur via transmission by the donor liver [10], but some donors with past exposure to HBV infection can be used selectively in some recipients [3].

HCV is the most common indication for LT, and at current it accounts for 40–50% of individuals on waiting lists [11–13]. About 5% of all potential organ donors are positive for HCV [14]. To date, one of the most controversial issues regarding extended-criteria donors has revolved around the potential positive impact of HCV-infected donors on short-term outcomes [15]. In Europe, the prevalence of anti-HBc-positive grafts reaches as much as 10% in some regions [5, 9, 16]. A multivariate analysis of the United Network for Organ Sharing database revealed that the use of anti-HBc-positive grafts is not an independent determinant of graft or patient survival [17]. There is a trend towards increasing the use of HCV-positive donors [18]. One-year patient survival rates of 97% have been reported in recipients of HCVinfected livers compared with rates of 87% for recipients of organs meeting the United Network for Organ Sharing-approved criteria, with no differences in surgical conditions including warm and cold ischemia times between the two groups [19].

A significant number of organ donors have viral infections and the effect of using such organs is an important and timely question. In this chapter we describe the pathophysiological changes in sub-optimal donor livers with viral infections. In addition, post-operative outcomes after LT using sub-optimal donor livers with viral infections will be discussed. Therefore, I/R injury, hepatic inflammation and the different treatments used in recipients of donor livers with viral infections will be reviewed. Finally, we give details of the different experimental models of LT with viral infections. All of this may be useful to guide the design of appropriate experimental models of LT that resemble clinical conditions as much as possible, together with addressing the effective use of sub-optimal livers for transplant and the development of new protective strategies in the clinical setting of LT.

#### **2. Sub-optimal donor and fibrosis progression**

Many studies have reported the transmission of HBV from liver allografts of hepatitis B surface antigen (HBsAg)-negative, anti-HBc-positive donors [10, 20–28]. HBV within hepatocytes and passenger leukocytes in the anti-HBc allograft can be the source of infection in the HBsAg recipient [29]. It has been shown that employing liver grafts from these donors can transmit HBV infections to HBsAg-negative recipients and result in de novo hepatitis B at rates that are estimated to vary from 33 to 78% after LT in the absence of antiviral prophylaxis [8, 10, 21]. Similarly, there are many reports of the presence of occult HBV infection in HBsAg/anti-HBc donors. Meanwhile, detectable quantities of HBV DNA have been found to be present in only 5–10% of anti-HBc immunocompetent patients, irrespective of their anti-HBs status [30]. The replication capacity of HBV in the anti-HBc liver allograft is significantly increased after LT when recipients are administered high-dose steroids [29]. Several molecular mechanisms have been proposed to explain increased HBV replication in these patients: (1) a glucocorticoid-responsive element in the HBV genome and stimulation of HBV-dependent transcription by glucocorticoids [31]; (2) immunosuppression after LT suppresses virus-specific immune responses whereby after LT wild-type HBV is more frequently re-selected and this can result in better replication *New Perspectives on the Use of Sub-Optimal Donor Livers DOI: http://dx.doi.org/10.5772/intechopen.84160*

fitness of the virus; (3) mutations selected in the HBV preS region result in a cytotoxic HBV strain, which is associated with cholestatic hepatitis [32–34]. HBV infection leads to graft damage in most cases [8]. It has been speculated that a liver that already hosts occult HBV infection, as is the case in the majority of HBcAb-positive donors [35], is particularly liable to suffer rapidly progressive damage when infected by HCV when it encounters immunosuppression for LT [36]. Some studies found that the survival of recipients of anti-HBc livers was significantly reduced 4 years after LT compared with recipients of anti-HBc-negative livers [8, 10]. With a post-LT follow-up of 2–4 years, a minority of transplant recipients developed fibrosing cholestatic hepatitis or cirrhosis leading to allograft failure [37].

Recurrence rates of hepatitis C, manifested by mild chronic hepatitis, fibrosis or cirrhosis, have been reported to be 54.55% in HCV-positive donor grafts when compared with 41.74% in HCV-negative grafts [38]. Marroquin [39] showed that patient survival at 2 years was significantly higher in HCV-positive recipients of HCV-positive grafts than in HCV-positive recipients of HCV-negative grafts (90 vs. 70%). In contrast, other studies indicated that in patients with HCV-related liver disease, there was no significant difference in survival between patients who received an HCV-negative graft and those who received an HCV-negative graft [40]. Khapra et al. [41] suggested that patients receiving HCV-positive donor organs develop more fibrosis over time than those receiving HCV-negative grafts. Wang et al. [42] reported that recipients show progression in liver inflammation grade or fibrosis stage regardless of the HCV status of the donors, although a higher stage of liver inflammation and fibrosis was found in HCV-positive graft recipients at follow-up. Although histological injury in the allograft owing to HCV is exceedingly common, progression of HCV is variable: some individuals experience indolent disease, whereas others progress rapidly to cirrhosis and liver failure [43]. Recently, donor age has been recognized to play an important role after LT with HCV-positive grafts. Khapra et al. [41] reported that HCV-positive grafts aged ≥50 years showed higher rates of graft failure and death among HCV-positive recipients compared to HCV-negative grafts from donors of the same ages. In addition, HCV-positive grafts from advanced-age donors showed more advanced fibrosis than those from younger donors [44].

#### **3. I/R injury and organ dysfunction**

Ischemia-reperfusion (I/R) injury, a phenomenon in which cellular damage in a hypoxic organ is accentuated following the restoration of oxygen delivery [45–47], is a multifactorial process associated with organ dysfunction of liver failure after LT. Early graft dysfunction affects up to 22% of liver allografts, with up to 6% of patients developing primary graft non-function and requiring retransplantation [48]. The association of I/R injury with the severity of HCV has been reported by several authors but with conflicting results, since I/R may or may not influence virus recurrence [49]. Although I/R injury is the underlying cause of graft dysfunction in marginal organs [4], it remains an unexplored issue in HBV and HCV grafts from donors.

The process of organ harvesting, cold storage and reperfusion is itself damaging, causing significant oxidative injury that can result in primary nonfunction or increase immunogenicity, prejudicing long-term graft survival [50, 51]. The duration of ischemic rewarming during implantation surgery is a risk factor for the severity of recurrent HCV disease after LT. In patients with hepatitis submitted to LT, the calculated risk for recurrent HCV disease post-LT is 19% if the ischemic time is 30 min versus 65% if this time extends to 90 min [52]. Rewarming ischemic injury appears to cause severe injury that enhances reinfection of the allograft with HCV after reperfusion, eventually leading to hepatic fibrosis and cirrhosis in some patients. Conversely, it has also been reported that cold ischemia time was not a significant risk factor for recurrent HCV infection after LT [53]. Indeed, the authors indicated that rewarming duration during implantation of <10 min was associated with minimal recurrence, whereas a duration of >70 min was associated with moderate to severe recurrent hepatitis. This finding was supported by Velidedeoglu et al. [54] in a United Network for Organ Sharing database study that showed that a warm ischemia time of >90 min was associated with decreased graft survival in HCV-positive individuals [53].

The ischemia-reperfusion procedure itself causes apoptosis, so-called programmed cell death, in the first stages after LT [55], and it can be exacerbated by immunosuppressive drugs used in LT [56]. Balliardini et al. [56] mentioned that both hepatocellular apoptosis and cell proliferation are correlated with HCV infection. Sung et al. [57] suggested that HCV may also stimulate cell growth to counter the apoptosis and thus complete the replication cycle of HCV and produce infectious viral particles. Because the primary target cell for HCV replication in vivo is thought to be the hepatocyte, events that lead to hepatocyte proliferation may enhance HCV replication. Alternatively, HCV core proteins have been shown to interact with cellular promoters and regulators of cell growth, which may affect liver regeneration [58]. All these data suggest that liver regeneration associated with the processes associated with living related LT might affect HCV recurrence. Similarly, I/R injury associated with LT from brain dead donors is associated with apoptosis, whereas HCV is able to counteract apoptosis to increase hepatocyte proliferation. Further studies will be required to elucidate the effect of I/R on HCV recurrence as well as the effects of HCV on hepatic I/R injury associated with LT.

#### **4. Hepatic donor inflammation in response to viral infection**

The relationship between hepatocellular injury, hepatic regeneration, viral replicative activity, HCV antigen expression, and the pathologic host response remains unproven. Increased allograft damage is related to enhanced levels of known immune modulators, including interleukines 6 and 10. These cytokines are released in the milieu of injured or proliferating cells and it is known that they participate in the pathogenesis of HCV via increased viral activity, exaggerated host response, or both [59, 60]. Recurrent HCV is characterized by hepatocellular damage, infiltration of inflammatory cells into the liver, and tissue remodeling that ultimately results in progressive fibrosis and cirrhosis. Infiltrating inflammatory cells at the sites of liver injury secrete chemokines that stimulate hepatic stellate cells, these in turn proliferate and produce extracellular matrix proteins. These stellate cells are key players in recurrent HCV and can be activated by a number of stimuli in the liver transplant setting: production of ROS, secretion of cytokines by immune cells (acute rejection, CMV infection), hyperglycemia, and chronic cholestasis (biliary complications). The combination of a variety of factors explains the accelerated progression of fibrosis in HCV-infected liver transplant recipients [61]. Meanwhile, it should also be considered that the factors mentioned above are all generated as a consequence of hepatic I/R. Thus, it can be hypothesized that the mechanisms involved in hepatic I/R may exacerbate the negative post-operative outcomes induced by virus infection.

The mechanism by which the identified factors exert their undesirable effect on HCV recurrence presumably involves host-viral interactions. Since HCV is not directly cytopathic, HCV damage must be mediated by the host immune response. Both CD4- and CD8-positive T-cells participate in the recognition of HCV peptide displayed by infected hepatocytes [62]. In studies using an animal model of acute hepadnavirus infection, using woodchuck HBV, Guo et al. [63] found that viral

*New Perspectives on the Use of Sub-Optimal Donor Livers DOI: http://dx.doi.org/10.5772/intechopen.84160*

clearance occurred following the appearance of CD4 and CD8 T-cells as well as the production of interferon gamma and tumor necrosis factor alpha within the infected liver. This was accompanied by a significant increase in apoptosis and regeneration of hepatocytes. HCV infection initiates a specific host response that is ineffective at clearing virus and results in hepatic cellular damage in a nonspecific fashion [53, 64]. The recurrence of HCV is accelerated after LT as a result of high viral loads and an exaggeration of this host response, which occurs even in the presence of exogenous immunosuppression. The alloimmune response and I/R injury may also contribute [53, 65]. Despite the limited information on inflammation and post-transplant viral recurrence, there is a need for a greater understanding of the relationship between the virus and inflammatory processes associated with either I/R or virus infection by itself. This can progress to irreversible liver damage, and is also a relevant issue for the livers of donors infected by virus (HBV and HCV), which are usually in a constant inflammatory state.

## **5. Viral kinetics and target treatment**

Despite being widely described in the literature, viral kinetics before, during and after LT using donor grafts with viral hepatitis has never been analyzed. The subject has only been considered in healthy livers transplanted into recipients with hepatitis. Thus investigations have mainly focused on the life cycle of the viruses and the recurrence of hepatitis.



*LT, liver transplantation; DAA, direct-acting antivirals; HBV, hepatitis B virus; HCV, hepatitis C virus; HBc, hepatitis B core antigen (anti-HBc); HBsAg, hepatitis B surface antigen.*

#### **Table 1.**

*Pharmacological strategies used in patient after or before the transplantation.*

In patients with hepatitis undergoing LT, HCV viral load decreases during the anhepatic phase and after graft reperfusion because of a lack of virus production, blood loss, and hepatic viral clearance. Despite the decline in viral load, hepatitis C virions continue to circulate and rapidly infect the new graft. HCV replication in the liver graft begins within a few hours after LT in most patients [66], and viral load increases as early as 12 h after graft reperfusion. The rapid increase in HCV viral load indicates that viral replication is highly efficient after LT and proves the high capacity of HCV to adapt to a completely new environment. However, HCV kinetics did not follow the same pattern in all patients. Differences in the immunosuppressive regimen appeared to influence HCV kinetics immediately after LT [66]. In fact, HCV-RNA concentrations increased rapidly in patients receiving corticosteroids as part of their immunosuppressive therapy [67–69], whereas they continued to decrease in most patients who were not receiving corticosteroids. Although this observation requires confirmation in further studies, it is possible that some immunosuppressive regimens might be more appropriate in the case of early antiviral therapy to eradicate HCV [66]. Powers et al. [70] estimated that viral resurgence begins when much less than 1% of the engrafted liver's hepatocytes are infected, suggesting that antiviral therapy should begin soon after, or before, LT in order to prevent or delay reinfection.

**Table 1** summarizes the pharmacological strategies used in patients before and after LT.

#### **6. Experimental models**

To the best of our knowledge, most of the current experimental models of hepatitis do not focus on LT. The only two experimental studies involving hepatitis and LT were by Dahmen et al. [71, 72], and both report severe hepatitis virus reinfection after woodchuck LT (**Table 2**). However, both studies focused on vaccines and not on the effects of I/R on viral infections after LT.


**Table 2.**

*Experimental studies with hepatitis virus reinfection after liver transplantation.*

## **7. Conclusion**

A shortage of donor organs remains a major obstacle to the widespread application of LT in patients with end-stage liver disease [73, 74]. This shortage could be alleviated by routine use of sub-optimal donor livers including those from donors with viral infections, although infection of the graft is almost universal and can lead to chronic hepatitis, cirrhosis, and graft failure. As stated in this chapter, studies on LT using sub-optimal donor grafts with viral infections have mainly focused on survival and the recurrence rates of hepatitis. In addition, although I/R injury is the underlying cause of graft dysfunction in sub-optimal donor livers with viral infections [4], it remains an unexplored issue in recipients transplanted with HBV and HCV grafts. It should be considered that the mechanisms involved in hepatic I/R depend on the conditions used during surgery, such as the period of ischemia (ranging from minutes to days) and the subclinical condition of the graft (healthy, sub-optimal, aged, etc.). However, clinical studies that focus on the pathological effects of I/R were only performed in recipients with viral infections from healthy liver grafts. In our view, multicenter clinical studies and experimental studies of LT using grafts with viral infections are needed to identify the inflammation associated with I/R and that induced by virus infection. The clinical application of strategies designed to increase the use of sub-optimal liver grafts with virus infection will depend on the use of experimental models of LT using donors with viral infections that resemble clinical conditions as much as possible [75]. We recognize that this may be difficult; however, multidisciplinary research groups should devote additional efforts to better understand the pathophysiology of LT using donors with viral infections to ultimately develop effective therapeutic strategies aimed at improving graft viability and at significantly increasing the organ donor pool.

### **Acknowledgements**

This research was supported by the Ministerio de Economía y Competitividad (project grant SAF-2015-64857-R) Madrid, Spain; the European Union (FondosFeder, "una manera de hacer Europa"); by CERCA Program/Generalitat de Catalunya; by the Secretaria d'Universitats i Recerca (Grant 2017SGR-551) Barcelona, Spain. ME Cornide-Petronio has a Sara Borrell contract from the Instituto de Salud Carlos III (Grant CD15/00129), Madrid, Spain. M Mendes-Braz is the recipient of a fellowship from São Paulo Research Foundation (Grant 2018/04625-9), São Paulo, Brazil. MB Jiménez-Castro has a contract from the Programa de Promoción del talento y su empleabilidad from the Ministerio de Economía y Competitividad

(Grant EMP-TU-2015-4167), Madrid, Spain. J Gracia-Sancho received continuous funding from the Instituto de Salud Carlos III (currently FIS PI17/00012) & the CIBEREHD, from Ministerio de Ciencia, Innovación y Universidades.

## **Conflict of interest**

The authors declare that they have no conflict of interest.

## **Author details**

Maria Eugenia Cornide-Petronio1 , Mariana Mendes-Braz1,2, Mónica B. Jiménez-Castro3 , Jordi Gracia-Sancho4 and Carmen Peralta1,5,6\*

1 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

2 Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences of University Sao Paulo (FCF/USP), São Paulo, SP, Brazil

3 Transplant Biomedicals, S.L., Barcelona, Spain

4 Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain

5 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain

6 Facultad de Medicina, Universidad International de Cataluña, Barcelona, Spain

\*Address all correspondence to: cperalta@clinic.ub.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*New Perspectives on the Use of Sub-Optimal Donor Livers DOI: http://dx.doi.org/10.5772/intechopen.84160*

## **References**

[1] Baumann AJ, Wheeler DS, James M, Turner R, Siegel A, Navarro VJ. Benefit of early palliative care intervention in end-stage liver disease patients awaiting liver transplantation. Journal of Pain and Symptom Management. 2015;**50**(6):882-886.e2. DOI: 10.1016/j. jpainsymman.2015.07.014

[2] Knaak J, McVey M, Bazerbachi F, Goldaracena N, Spetzler V, Selzner N, et al. Liver transplantation in patients with end-stage liver disease requiring intensive care unit admission and intubation. Liver Transplantation. 2015;**21**(6):761-767. DOI: 10.1002/lt.24115

[3] Jimenez-Castro M, Elias-Miró M, Peralta C. Expanding the donor pool in liver transplantation: Influence of ischemia-reperfusion. In: Saidi RF, editor. Organ Donation and Organ Donors: Issues. New York: NOVA Science Publishers, Inc; 2013. p. 41-82

[4] Busuttil RW, Tanaka K. The utility of marginal donors in liver transplantation. Liver Transplantation. 2003;**9**(7): 651-663. DOI: 10.1053/jlts.2003.50105

[5] Gallegos-Orozco JF, Vargas HE, Rakela J. Virologically compromised donor grafts in liver transplantation. Journal of Hepatology. 2004;**41**(4): 512-521. DOI: 10.1016/j.jhep.2004.08.003

[6] Bacchella T, Galvão FHF, Almeida JLJ, Figueira ER, Moraes A, Machado MCC. Marginal grafts increase early mortality in liver transplantation. São Paulo Medical Journal. 2008;**126**(3):161-165. DOI: 10.1590/ S1516-31802008000300005

[7] Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. Journal of Viral Hepatitis. 2004;**11**(2):97-107. DOI: 10.1046/j.1365-2893.2003.00487.x

[8] Prieto M, Gómez MD, Berenguer M, Córdoba J, Rayón JM, Pastor M, et al. De novo hepatitis B after liver transplantation from hepatitis B core antibody-positive donors in an area with high prevalence of anti-HBc positivity in the donor population. Liver Transplantation. 2001;**7**(1):51-58. DOI: 10.1053/jlts.2001.20786

[9] Nickkholgh A, Weitz J, Encke J, Sauer P, Mehrabi A, Büchler MW, et al. Utilization of extended donor criteria in liver transplantation: A comprehensive review of the literature. Nephrology Dialysis Transplantation. 2007;**22**(s8):viii29-viii36. DOI: 10.1093/ndt/gfm654

[10] Dickson RC, Everhart JE, Lake JR, Wei Y, Seaberg EC, Wiesner RH, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Gastroenterology. 1997;**113**(5):1668-1674. DOI: 10.1053/ gast.1997.v113.pm9352871

[11] Roth D, Fernandez JA, Babischkin S, De Mattos A, Buck BE, Quan S, et al. Detection of hepatitis C virus infection among cadaver organ donors: Evidence for low transmission of disease. Annals of Internal Medicine. 1992;**117**(6):470-475

[12] Candinas D, Joller-Jemelka HI, Schlumpf R, Wicki A, Mutimer DJ, Keusch G, et al. Hepatitis C RNA prevalence in a Western European organ donor pool and virus transmission by organ transplantation. Journal of Medical Microbiology. 1994;**41**(4):220-223. DOI: 10.1099/00222615-41-4-220

[13] Trotter JF. Expanding the donor pool for liver transplantation.

Current Gastroenterology Reports. 2000;**2**(1):46-54

[14] López-Navidad A, Caballero F. Extended criteria for organ acceptance. Strategies for achieving organ safety and for increasing organ pool. Clinical Transplantation. 2003;**17**(4):308-324

[15] Jiménez-Castro MB, Gracia-Sancho J, Peralta C. Brain death and marginal grafts in liver transplantation. Cell Death & Disease. 2015;**6**:e1777. DOI: 10.1038/cddis.2015.147

[16] Roque-Afonso AM, Feray C, Samuel D, Simoneau D, Roche B, Emile JF, et al. Antibodies to hepatitis B surface antigen prevent viral reactivation in recipients of liver graftsfrom anti-HBC positive donors. Gut. 2002;**50**(1):95-99

[17] Yu L, Koepsell T, Manhart L, Ioannou G. Survival after orthotopic liver transplantation: The impact of antibody against hepatitis B core antigen in the donor. Liver Transplantation. 2009;**15**(10):1343-1350. DOI: 10.1002/ lt.21788

[18] Velidedeoglu E, Desai NM, Campos L, Olthoff KM, Shaked A, Nunes F, et al. The outcome of liver grafts procured from hepatitis C-positive donors. Transplantation. 2002;**73**(4):582-587

[19] Mukherjee S, Sorrell MF. Controversies in liver transplantation for hepatitis C. Gastroenterology. 2008;**134**(6):1777-1788. DOI: 10.1053/j. gastro.2008.02.035

[20] Castells L, Vargas V, Rodríguez-Frías F, Allende H, Jardí R, Margarit C, et al. Transmission of hepatitis B virus by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Transplantation Proceedings. 1999;**31**(6):2464-5246

[21] Dodson SF, Issa S, Araya V, Gayowski T, Pinna A, Eghtesad B, et al. Infectivity of hepatic allografts with antibodies to hepatitis B virus. Transplantation. 1997;**64**(11):1582-1584

[22] Dodson SF, Bonham CA, Geller DA, Cacciarelli TV, Rakela J, Fung JJ. Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors. Transplantation. 1999;**68**(7):1058-1061

[23] Douglas DD, Rakela J, Wright TL, Krom RA, Wiesner RH. The clinical course of transplantation-associated de novo hepatitis B infection in the liver transplant recipient. Liver Transplantation and Surgery. 1997;**3**(2):105-111

[24] Lowell JA, Howard TK, White HM, Shenoy S, Huettner PC, Brennan DC, et al. Serological evidence of past hepatitis B infection in liver donor and hepatitis B infection in liver allograft. Lancet. 1995;**345**(8957):1084-1085

[25] Roche B, Samuel D, Gigou M, Feray C, Virot V, Schmets L, et al. De novo and apparent de novo hepatitis B virus infection after liver transplantation. Journal of Hepatology. 1997;**26**(3):517-526

[26] Smith H, Gibbs P. Hepatitis B, the hidden danger in cadaveric organ donors. Transplantation. 2000;**69**(3):458-459

[27] Uemoto S, Inomata Y, Sannomiya A, Koshiba T, Kurokawa T, Takatsuki M, et al. Posttransplant hepatitis B infection in liver transplantation with hepatitis B core antibody-positive donors. Transplantation Proceedings. 1998;**30**(1):134-135

[28] Uemoto S, Sugiyama K, Marusawa H, Inomata Y, Asonuma K, Egawa H, et al. Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living related liver transplants. Transplantation. 1998;**65**(4):494-499

*New Perspectives on the Use of Sub-Optimal Donor Livers DOI: http://dx.doi.org/10.5772/intechopen.84160*

[29] Yu AS, Vierling JM, Colquhoun SD, Arnaout WS, Chan CK, Khanafshar E, et al. Transmission of hepatitis B infection from hepatitis B core antibody-positive liver allografts is prevented by lamivudine therapy. Liver Transplantation. 2001;**7**(6):513-517. DOI: 10.1053/jlts.2001.23911

[30] Van Thiel DH, De Maria N, Colantoni A, Friedlander L. Can hepatitis B core antibody positive livers be used safely for transplantation: Hepatitis B virus detection in the liver of individuals who are hepatitis B core antibody positive. Transplantation. 1999;**68**(4):519-522

[31] Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proceedings of the National Academy of Sciences of the United States of America. 1986;**83**(6):1627-1631

[32] Bock CT, Tillmann HL, Maschek HJ, Manns MP, Trautwein C. A preS mutation isolated from a patient with chronic hepatitis B infection leads to virus retention and misassembly. Gastroenterology. 1997;**113**(6):1976-1982

[33] Trautwein C, Schrem H, Tillmann HL, Kubicka S, Walker D, Böker KH, et al. Hepatitis B virus mutations in the pre-S genome before and after liver transplantation. Hepatology. 1996;**24**(3):482-488

[34] Samuel D, Forns X, Berenguer M, Trautwein C, Burroughs A, Rizzetto M, et al. Report of the monothematic EASL conference on liver transplantation for viral hepatitis (Paris, France, January 12-14, 2006). Journal of Hepatology. 2006;**45**(1):127-143. DOI: 10.1016/j. jhep.2006.05.001

[35] Raimondo G, Navarra G, Mondello S, Costantino L, Colloredo G, Cucinotta E, et al. Occult hepatitis B virus in liver tissue of individuals without

hepatic disease. Journal of Hepatology. 2008;**48**(5):743-746. DOI: 10.1016/j. jhep.2008.01.023

[36] Tandoi F, Romagnoli R, Martini S, Mazza E, Nada E, Cocchis D, et al. Outcomes of liver transplantation in simultaneously hepatitis B surface antigen and hepatitis C virus RNA positive recipients: The deleterious effect of donor hepatitis B core antibody positivity. Transplantation Proceedings. 2012;**44**(7):1960-1962. DOI: 10.1016/j. transproceed.2012.07.061

[37] Muñoz SJ. Use of hepatitis B core antibody-positive donors for liver transplantation. Liver Transplantation. 2002;**8**(10 Suppl 1):S82-S87. DOI: 10.1053/jlts.2002.35783

[38] Testa G, Goldstein RM, Netto G, Abbasoglu O, Brooks BK, Levy MF, et al. Long-term outcome of patients transplanted with livers from hepatitis C-positive donors. Transplantation. 1998;**65**(7):925-929

[39] Marroquin CE, Marino G, Kuo PC, Plotkin JS, Rustgi VK, Lu AD, et al. Transplantation of hepatitis C-positive livers in hepatitis C-positive patients is equivalent to transplanting hepatitis C-negative livers. Liver Transplantation. 2001;**7**(9):762-768

[40] Ghobrial RM, Steadman R, Gornbein J, Lassman C, Holt CD, Chen P, et al. A 10-year experience of liver transplantation for hepatitis C: Analysis of factors determining outcome in over 500 patients. Annals of Surgery. 2001;**234**(3):384-393

[41] Khapra AP, Agarwal K, Fiel MI, Kontorinis N, Hossain S, Emre S, et al. Impact of donor age on survival and fibrosis progression in patients with hepatitis C undergoingliver transplantation using HCV+ allografts. Liver Transplantation. 2006;**12**(10):1496-1503. DOI: 10.1002/ lt.20849

[42] Wang W, Niu Y, Yue Y, Wang L, Liu Y, Chen H, et al. Selection of liver graft from HCV-positive donor and prognosis of liver transplant recipients. International Journal of Clinical and Experimental Pathology. 2016;**9**(10):10817-10823

[43] Brown RS. Hepatitis C and liver transplantation. Nature. 2005;**436**(7053):973-978. DOI: 10.1038/ nature04083

[44] Gastaca M. Extended criteria donors in liver transplantation: Adapting donor quality and recipient. Transplantation Proceedings. 2009 Apr;**41**(3):975-979. DOI: 10.1016/j. transproceed.2009.02.016

[45] Jaeschke H. Mechanisms of reperfusion injury after warm ischemia of the liver. Journal of Hepato-Biliary-Pancreatic Surgery. 1998;**5**(4):402-408

[46] Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: Pathogenic mechanisms and basis for hepatoprotection. Journal of Gastroenterology and Hepatology. 2003;**18**(8):891-902

[47] Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2003;**284**(1):G15-G26

[48] Ploeg RJ, D'Alessandro AM, Knechtle SJ, Stegall MD, Pirsch JD, Hoffmann RM, et al. Risk factors for primary dysfunction after liver transplantation—A multivariate analysis. Transplantation. 1993;**55**(4):807-813

[49] Killackey MT, Gondolesi GE, Liu LU, Paramesh AS, Thung SN, Suriawinata A, et al. Effect of ischemia-reperfusion on the incidence of acute cellular rejection and timing of histologic hepatitis C virus

recurrence after liver transplantation. Transplantation Proceedings. 2008;**40**(5):1504-1510. DOI: 10.1016/j. transproceed.2008.03.101

[50] Schemmer P, Mehrabi A, Kraus T, Sauer P, Gutt C, Uhl W, et al. New aspects on reperfusion injury to liver— Impact of organ harvest. Nephrology, Dialysis, Transplantation. 2004;**19** Suppl 4:iv26-iv35

[51] Kiuchi T, Oldhafer KJ, Schlitt HJ, Nashan B, Deiwick A, Wonigeit K, et al. Background and prognostic implications of perireperfusion tissue injuries in human livertransplants: A panel histochemical study. Transplantation. 1998;**66**(6):737-747

[52] Baron PW, Sindram D, Higdon D, Howell DN, Gottfried MR, Tuttle-Newhall JE, et al. Prolonged rewarming time during allograft implantation predisposes to recurrent hepatitis C infection after liver transplantation. Liver Transplantation. 2000;**6**(4):407-412

[53] Watt KD, Lyden ER, Gulizia JM, McCashland TM. Recurrent hepatitis C posttransplant: Early preservation injury may predict poor outcome. Liver Transplantation. 2006;**12**(1):134-139. DOI: 10.1002/lt.20583

[54] Velidedeoglu E, Mange KC, Frank A, Abt P, Desai NM, Markmann JW, et al. Factors differentially correlated with the outcome of liver transplantation in HCV+ and HCV− recipients. Transplantation. 2004;**77**(12):1834-1842

[55] Borghy-Scoazec G, Scoazec JY, Durand F, Bernuau J, Belghiti J, Feldmann G, et al. Apoptosis after ischemia-reperfusion in human liver allografts. Liver Transplantation and Surgery. 1997;**3**:407-415

[56] Ballardini G, De Raffele E, Groff P, Bioulac-Sage P, Grassi A, Ghetti S,

#### *New Perspectives on the Use of Sub-Optimal Donor Livers DOI: http://dx.doi.org/10.5772/intechopen.84160*

et al. Timing of reinfection and mechanisms of hepatocellular damage in transplanted hepatitis C virusreinfected liver. Liver Transplantation. 2002;**8**(1):10-20. DOI: 10.1053/ jlts.2002.30141

[57] Sung VM, Shimodaira S, Doughty AL, Picchio GR, Can H, Yen TS, et al. Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: The apoptotic effects of virus infection. Journal of Virology. 2003;**77**(3):2134-2146

[58] Olthoff KM. Hepatic regeneration in living donor liver transplantation. Liver Transplantation. 2003;**9**(10 Suppl 2):S35-S41

[59] Molmenti EP, Klintmalm GBG. Hepatitis C recurrence after liver transplantation. Liver Transplantation. 2000;**6**(4):413-414. DOI: 10.1053/jlts. 2000.8203

[60] Cameron AM, Ghobrial RM, Hiatt JR, Carmody IC, Gordon SA, Farmer DG, et al. Effect of nonviral factors on hepatitis C recurrence after liver transplantation. Annals of Surgery. 2006;**244**(4):563-571. DOI: 10.1097/01. sla.0000237648.90600.e9

[61] Crespo G, Mariño Z, Navasa M, Forns X. Viral hepatitis in liver transplantation. Gastroenterology. 2012;**142**(6):1373-1383.e1. DOI: 10.1053/j.gastro.2012.02.011

[62] Rosen HR, Hinrichs DJ, Gretch DR, Koziel MJ, Chou S, Houghton M, et al. Association of multispecific CD4(+) response to hepatitis C and severity of recurrence after livertransplantation. Gastroenterology. 1999;**117**(4):926-932

[63] Guo JT, Zhou H, Liu C, Aldrich C, Saputelli J, Whitaker T, et al. Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections. Journal of Virology. 2000;**74**(3):1495-1505

[64] Rico MA, Quiroga JA, Subirá D, Garcia E, Castañón S, Sällberg M, et al. Features of the CD4+ T-cell response in liver and peripheral blood of hepatitis C virus-infected patients with persistently normal and abnormal alanine aminotransferase levels. Journal of Hepatology. 2002;**36**(3):408-416

[65] McCaughan GW, Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation. Journal of Hepatology. 2004;**40**(3):368-374

[66] Garcia-Retortillo M, Forns X, Feliu A, Moitinho E, Costa J, Navasa M, et al. Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology. 2002;**35**(3):680-687. DOI: 10.1053/jhep.2002.31773

[67] Guilera M, Forns X, Torras X, Enríquez J, Coll S, Solà R, et al. Pretreatment with prednisolone does not improve the efficacy of subsequent alpha interferon therapy in chronic hepatitis C. Journal of Hepatology. 2000;**33**(1):135-141

[68] Tisone G, Angelico M, Palmieri G, Pisani F, Anselmo A, Baiocchi L, et al. A pilot study on the safety and effectiveness of immunosuppression without prednisone after liver transplantation. Transplantation. 1999;**67**(10):1308-1313

[69] McHutchison JG, Ponnudurai R, Bylund DL, Anguiano A, Pockros PJ, Mondala T, et al. Prednisone withdrawal followed by interferon alpha for treatment of chronic hepatitis C infection: Results of a randomized controlled trial. Journal of Clinical Gastroenterology. 2001;**32**(2):133-137

[70] Powers KA, Ribeiro RM, Patel K, Pianko S, Nyberg L, Pockros P, et al. Kinetics of hepatitis C virus reinfection after liver transplantation. Liver Transplantation. 2006;**12**(2):207-216. DOI: 10.1002/lt.20572

[71] Dahmen U, Li J, Dirsch O, Fiedler M, Lu M, Roggendorf M, et al. A new model of hepatitis B virus reinfection: Liver transplantation in the woodchuck1. Transplantation. 2002;**74**(3):373-380

[72] Dahmen U, Dirsch O, Li J, Fiedle M, Lu M, Rispeter K, et al. Adoptive transfer of immunity: A new strategy to interfere with severe hepatitis virus reinfection after woodchuck liver transplantation. Transplantation. 2004;**77**(7):965-972

[73] Uchiyama H, Yanaga K, Nishizaki T, Soejima Y, Yoshizumi T, Sugimachi K. Effects of deletion variant of hepatocyte growth factor on reduced-size liver transplantation in ratsTransplantation. 1999;**68**(1):39-44

[74] Cornide-Petronio ME, Casillas-Ramírez A, Jiménez-Castro MB, Peralta C. Experimental brain death models in liver transplantation. In: Tsoulfas G, editor. Organ Donation and Transplantation. London: IntechOpen; 2018. pp. 136-151

[75] Gracia-Sancho J, Casillas-Ramírez A, Peralta C. Molecular pathways in protecting the liver from ischaemia/ reperfusion injury: A 2015 update. Clinical Science (London, England). 2015;**129**(4):345-362. DOI: 10.1042/ CS20150223

[76] Chen YS, Wang CC, de Villa VH, Wang SH, Cheng YF, Huang TL, et al. Prevention of de novo hepatitis B virus infection in living donor liver transplantation using hepatitis B core antibody positive donors. Clinical Transplantation. 2002;**16**(6):405-409

[77] Manzarbeitia C, Reich DJ, Ortiz JA, Rothstein KD, Araya VR, Munoz SJ. Safe use of livers from donors with positive hepatitis B core antibody. Liver Transplantation. 2002;**8**(6):556-561. DOI: 10.1053/jlts.2002.33451

[78] Nery JR, Nery-Avila C, Reddy KR, Cirocco R, Weppler D, Levi DM, et al.

Use of liver grafts from donors positive for antihepatitis B-core antibody (anti-HBc) in the era of prophylaxis with hepatitis-B immunoglobulin and lamivudine. Transplantation. 2003;**75**(8):1179-1186

[79] Prakoso E, Strasser SI, Koorey DJ, Verran D, McCaughan GW. Long-term lamivudine monotherapy prevents development of hepatitis B virus infection in hepatitis B surface-antigen negative liver transplant recipients from hepatitis B core-antibody-positive donors. Clinical Transplantation. 2006;**20**(3):369-373. DOI: 10.1111/j.1399-0012.2006.00495.x

[80] Fábrega E, García-Suarez C, Guerra A, Orive A, Casafont F, Crespo J, et al. Liver transplantation with allografts from hepatitis B core antibody-positive donors: A new approach. Liver Transplantation. 2003;**9**(9):916-920. DOI: 10.1053/jlts.2003.50190

[81] Kwon CHD, Suh KS, Yi NJ, Chang SH, Cho YB, Cho JY, et al. Longterm protection against hepatitis B in pediatric liver recipients can be achieved effectively with vaccination after transplantation. Pediatric Transplantation. 2006;**10**(4):479-486. DOI: 10.1111/j.1399-3046.2006.00540.x

[82] Umeda M, Marusawa H, Ueda M, Takada Y, Egawa H, Uemoto S, et al. Beneficial effects of short-term lamivudine treatment for de novo hepatitis B virus reactivation after liver transplantation. American Journal of Transplantation. 2006;**6**(11):2680-2685. DOI: 10.1111/j.1600-6143.2006.01542.x

[83] Suehiro T, Shimada M, Kishikawa K, Shimura T, Soejima Y, Yoshizumi T, et al. Prevention of hepatitis B virus infection from hepatitis B core antibody-positive donor graft using hepatitis B immune globulin and lamivudine in living donor liver transplantation. Liver International. 2005;**25**(6):1169-1174. DOI: 10.1111/j.1478-3231.2005.01165.x

*New Perspectives on the Use of Sub-Optimal Donor Livers DOI: http://dx.doi.org/10.5772/intechopen.84160*

[84] Hwang S, Lee SG, Park KM, Kim KH, Ahn CS, Oh HB, et al. Five-year follow-up of a hepatitis B virus-positive recipient of hepatitis B surface antigenpositive living donor liver graft. Liver Transplantation. 2006;**12**(6):993-997. DOI: 10.1002/lt.20799

[85] Chhatwal J, Samur S, Bethea ED, Ayer T, Kanwal F, Hur C, et al. Transplanting hepatitis C viruspositive livers into hepatitis C virusnegative patients with preemptive antiviral treatment: A modeling study. Hepatology. 2018;**67**(6):2085-2095. DOI: 10.1002/hep.29723

[86] Campos-Varela I, Agudelo EZ, Sarkar M, Roberts JP, Terrault NA. Use of a hepatitis C virus (HCV) RNA-positive donor in a treated HCV RNA-negative liver transplant recipient. Transplant Infectious Disease. 2018;**20**(1):1-8. DOI: 10.1111/tid.12809

[87] Saberi B, Hamilton JP, Durand CM, Li Z, Philosophe B, Cameron AM, et al. Utilization of hepatitis C virus RNA-positive donor liver for transplant to hepatitis C virus RNA-negative recipient. Liver Transplantation. 2018;**24**(1):140-143. DOI: 10.1002/ lt.24838

## *Edited by Georgios Tsoulfas*

Liver cirrhosis and its complications affect millions of patients of all ages around the globe and present treating physicians with perplexing problems, given the variety of etiologies and the critical nature of hepatic physiology. This book is a collection of chapters offering the distilled knowledge of various worldwide experts in hepatic surgery and hepatic physiology. The various debates that are presented regarding the diagnosis and treatment of liver cirrhosis and its significant complications, in addition to the most up-to-date information regarding molecular aspects, provide the reader with the full spectrum of knowledge in this challenging and continuously evolving field.

Published in London, UK © 2019 IntechOpen © Johanna Poetsch / iStock

Liver Cirrhosis - Debates and Current Challenges

Liver Cirrhosis

Debates and Current Challenges

*Edited by Georgios Tsoulfas*