Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2012)

Almost three decades have passed since the historical NIH consensus conference which paved the road for introduction of liver transplantation (LT) into routine clinical practice worldwide. Progress in technical and medical skills as well as development of potent anti-rejection agents led to a progressively improved long-term survival of patients who underwent LT, 20 and even 30 years ago. In the early years of liver transplantation, guideline driven protocol liver biopsies were used extensively to study the natural history, response to anti-rejection treatment, recurrence of the original liver disease and complications of LT. The cumulative experience gained through these investigations led to a number of conclusions [1Pappo O. Ramos H. Starzl T.E. et al.Structural integrity and identification of causes of liver allograft dysfunction occurring more than 5 years after transplantation.Am J Surg Pathol. 1995; 19: 192-206Crossref PubMed Scopus (119) Google Scholar, 2Neuberger J. Wilson P. Adams D. Protocol liver biopsies: the case in favour.Transplant Proc. 1998; 30: 1497-1499Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 3Mells G. Neuberger J. Protocol liver allograft biopsies.Transplantation. 2008; 85: 1686-1692Crossref PubMed Scopus (40) Google Scholar, 4Abraham S.C. Poterucha J.J. Rosen C.B. Demetris A.J. Krasinskas A.M. Histologic abnormalities are common in protocol liver allograft biopsies from patients with normal liver function tests.Am J Surg Pathol. 2008; 32: 965-973Crossref PubMed Scopus (62) Google Scholar, 5Mells G. Mann C. Hubscher S. Neuberger J. Late protocol liver biopsies in the liver allograft: a neglected investigation.Liver Transplant. 2009; 15: 931-938Crossref PubMed Scopus (63) Google Scholar, 6Hubscher S.G. What is the long-term outcome of the liver allograft?.J Hepatol. 2011; 55: 702-717Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 7Ekong U.D. The long-term liver graft and protocol biopsy: do we want to look? What will we find?.Curr Opin Organ Transplant. 2011; 16: 505-508Crossref PubMed Scopus (19) Google Scholar]: (1) Histo-pathologic abnormalities in relatively old grafts followed up to 15 years, did not necessarily correlate with disturbed standard liver function tests which may remain intact. (2) Routine liver function tests have a low specificity and sensitivity for diagnosis of rejection and remain an inaccurate mean for assessment of graft dysfunction. (3) Protocol liver biopsies performed several years after LT, at a time of normal liver function tests and in the absence of clinical signs, may unmask significant occult morbidities such as recurrence of autoimmune liver disease, including PBC and PSC, hepatitis C and advanced fibrosis, chronic rejection (i.e. central venulitis, bile duct loss and fibrosis) or non-alcoholic fatty liver disease. (4) Early recognition of histologic graft abnormalities may contribute to better control and improve survival in patients with overt or occult liver disease. (5) Unexplained idiopathic post-transplant chronic hepatitis (IPTH), nodular regenerative hyperplasia and hepatic structural changes including, hepatocyte disarray, perisinusoidal fibrosis, sinusoidal dilatation and peliosis hepatis have been reported in up to 30% of protocol liver biopsies performed ⩾5 years after transplantation. The practice of conducting protocol liver biopsies in LT patient has changed in the past decade. A recent non-formal survey conducted in 35 transplant centers reported by Mells et al. revealed that only 25% of centers continue the practice of periodic protocol liver graft biopsies at 1, 2, or 3, 5, 10 and 15 years post LT in non-HCV patients [[3]Mells G. Neuberger J. Protocol liver allograft biopsies.Transplantation. 2008; 85: 1686-1692Crossref PubMed Scopus (40) Google Scholar]. Thus, despite proven benefits documented by periodic protocol planned liver biopsies, criticism against such an approach has repeatedly been raised over the past 15 years and still is the driving force for repeated assessment of progressively growing databases [1Pappo O. Ramos H. Starzl T.E. et al.Structural integrity and identification of causes of liver allograft dysfunction occurring more than 5 years after transplantation.Am J Surg Pathol. 1995; 19: 192-206Crossref PubMed Scopus (119) Google Scholar, 2Neuberger J. Wilson P. Adams D. Protocol liver biopsies: the case in favour.Transplant Proc. 1998; 30: 1497-1499Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 3Mells G. Neuberger J. Protocol liver allograft biopsies.Transplantation. 2008; 85: 1686-1692Crossref PubMed Scopus (40) Google Scholar, 4Abraham S.C. Poterucha J.J. Rosen C.B. Demetris A.J. Krasinskas A.M. Histologic abnormalities are common in protocol liver allograft biopsies from patients with normal liver function tests.Am J Surg Pathol. 2008; 32: 965-973Crossref PubMed Scopus (62) Google Scholar, 5Mells G. Mann C. Hubscher S. Neuberger J. Late protocol liver biopsies in the liver allograft: a neglected investigation.Liver Transplant. 2009; 15: 931-938Crossref PubMed Scopus (63) Google Scholar, 6Hubscher S.G. What is the long-term outcome of the liver allograft?.J Hepatol. 2011; 55: 702-717Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 7Ekong U.D. The long-term liver graft and protocol biopsy: do we want to look? What will we find?.Curr Opin Organ Transplant. 2011; 16: 505-508Crossref PubMed Scopus (19) Google Scholar]. The arguments used by opponents of this practice include among others that histologic changes of variable severity identified through protocol liver biopsies in 5–90% of adult patients do not necessarily correlate with clinical manifestations or affect the management of patients; the possibility of sampling errors and inter-observer variability in interpretation; the risk, albeit low, of complications (morbidity with major complications 0.20–3.7% and mortality of 0.03–0.20%, determined in non transplant patients); the availability of new non-invasive techniques, which although non-validated yet, may enable reasonable assessment of degree of inflammation and fibrosis as well as reduction in cost. In contrast, proponents of protocol liver biopsies argue that such practice enables the early recognition of occult rejection or disease recurrence and consequently will lead to adjustment of immune-suppressive therapy; the fact that normal or almost normal liver histology may improve identification of LT patients who developed tolerance, thus enabling reduction or even discontinuation of immune suppression and it’s associated adverse effects. In the present issue of the Journal, Dr. Sebagh and co-workers have reviewed retrospectively a relatively large cohort of 91 LT patients who underwent protocol liver biopsies at 10, 15 and 20 years after transplantation [[8]Sebagh M. Samuel D. Antonini T. Coilly A. Esposti D.D. Roche B. et al.Twenty-year protocol liver biopsies: invasive but useful for the management of liver recipients.J Hepatol. 2012; 56: 86-93Abstract Full Text Full Text PDF Scopus (34) Google Scholar]. Fifty-six patients who were biopsied at 10 and/or 15 years and who did not undergo a protocol biopsy at year 20, served as controls. Until now, data on the natural history of graft histology was available mainly for periods up to 10 years (and in a few cases 15 years) after LT. The main contribution of the present study is additional new information extending the long-term histologic follow-up in such patients who underwent LT for a variety of indications. As expected, only 10% of patients had normal or almost normal graft histology. Overall abnormal histologic findings rose from 65% and 80% at 5 and 10 years post LT, respectively, to 90% at 20 years. At 20 years post LT, evidence for progressive liver injury over time was detected in about one third of patients who had more than one pathological disorder (combined disorders) as compared to only 7% and 17% at 5 and 10 years post LT, respectively. The rate of structural changes was 20% at year 20 and contributed significantly to the overall rise in abnormal histologic findings over time. The most common etiology for histologic disorders in the study cohort was viral liver disease (HBV and HCV) with a substantial number of patients who acquired viral infection post LT. The second most common etiology was chronic rejection. Importantly, results obtained through protocol liver biopsies lead in part to modification of immunosuppression regimens in 35% of patients. These findings provide support for proponents of protocol liver biopsies even at 20 years post LT since they have a potential impact on patient’s management. Other observations from the present study suggest that non-invasive techniques such as FibroTest-Acti Test and transient elastography are still not reliable enough to diagnose the precise stage of fibrosis in the graft as compared to the gold standard of a liver biopsy. Although this is a retrospective study and selection of patients and controls has not been prospectively randomized, the report contains a wealth of information which should interest hepatologists, surgeons and pathologists alike who take care of LT patients. In summary, the study of Sebagh et al. suggests that “late” protocol liver biopsies are important for broadening our knowledge on the natural history, progression, management and prognosis of the graft in LT patients, even at 20 years after transplantation. Furthermore, individual benefit has been documented in about one third of patients who underwent a protocol liver biopsy which contributed to their management. Finally, LT patients who do not present with clinical or laboratory signs of hepatic dysfunction may have smoldering occult disease and therefore may benefit from protocol biopsies even 2 decades after transplantation. Yet, despite all justifications, it is not realistic to expect that late protocol liver biopsies will be accepted overwhelmingly by the individual patients (or physicians) without clinical evidence for hepatic dysfunction. However, protocol liver biopsies remain an important tool for management of LT patients and most probably will continue in large and designated transplant centers worldwide. The author declared that they he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.