Serial liver biopsies: a gateway into understanding the long-term health of the liver allograft
Article Outline
The place of liver histology in the ongoing management of liver transplant patients has changed in concert with the prevailing preoccupations of liver transplant surgeons and physicians. The early papers on liver transplantation were dominated by concerns regarding allograft rejection. As liver transplantation became established in man, the histological correlates of acute cellular rejection were clarified by Snover, after which the same histological features became the basis for diagnosis [1]. Since then, the Banff group has bought uniformity to reporting practices for acute cellular and chronic ductopenic rejection [2], [3].
The diagnosis of acute cellular rejection in a liver allograft requires a liver biopsy. The decision to biopsy an allograft is usually prompted by abnormalities in the clinical data. In addition, some programs carry out biopsies, often referred to as ‘protocol biopsies’, on a planned schedule irrespective of liver chemistries. Protocol biopsies, especially those procured in the first few weeks after transplantation when acute cellular rejection is most common, may identify subclinical degrees of acute cellular rejection [4]. The benefits of, or indeed need for, treatment of subclinical rejection are controversial [5]. The clinical utility of protocol liver biopsies after the initial few weeks remains even less established. When one considers that liver biopsies carry a risk of morbidity and mortality [6], are inconvenient for the patient, and stretch the resources of available gastroenterologists, hepatologists or radiologists, it is easy to understand why protocol liver biopsies have fallen by the wayside in many active liver transplant programs.
There is another value to protocol biopsies of the allograft, particularly when repeated regularly after transplantation. Two recent publications highlight the potential for serial biopsies to shed light on slowly evolving pathological processes in functioning allografts. The liver transplant team at the Mayo Clinic in Rochester Minnesota has continued to carry out protocol liver biopsies on many long-term survivors. Maor-Kindler and colleagues from that group have reported recently on the histological appearances in patients whose pre-transplant diagnosis was cryptogenic cirrhosis, and compared the results over 4 years with patients transplanted for chronic hepatitis C infection, cholestatic liver disease or alcoholic liver disease [7]. They found that histological features of inflammation and fibrosis were more prevalent in the group of patients with hepatitis C than in the three control groups, at all time points after transplantation. Furthermore, both inflammation and fibrosis increased in prevalence and severity between 4 months and 1 year among hepatitis C-infected recipients. In contrast, inflammatory activity declined over time among the patients transplanted for cryptogenic cirrhosis. Similarly, among alcoholic liver transplant recipients, there was a trend towards less inflammation in the most recent biopsy taken an average of 40 months post transplantation, compared to that in the protocol biopsy at 4 months.
An interesting observation was that steatosis, defined as greater than or equal to 2 on a qualitative scale, increased over time among patients transplanted for cryptogenic cirrhosis. Whereas 8% of patients with a prior diagnosis of cryptogenic cirrhosis had steatosis in protocol biopsies taken at 4 months, this prevalence had risen to 38% by the most recent biopsy an average of 47 months after transplantation. There was no similar trend among any of the other diagnostic groups. These data can be interpreted as supportive of the notion that cryptogenic cirrhosis is a manifestation of a disorder of lipid metabolism, and not clandestine hepatitis C, and that steatosis observed at 47 months is a manifestation of recurrence of the underlying disorder.
In Maor-Kindler's study, only alcoholic patients with serial negative measures of alcohol use were included. Thus the contribution of alcohol relapse to histology could not be assessed. Burra and colleagues addressed the impact of alcohol relapse on allograft histology in the present issue of the Journal of Hepatology [8]. They allied serial protocol biopsies to appropriate serial measures of psychological health as assessed by a semistructured interview. Thirty-four alcoholics, who were long-term survivors of liver transplantation, were stratified according to ‘heavy alcohol use, occasional alcohol use or no alcohol use’. As in previous studies, Burra et al. found that alcohol relapse was relatively uncommon in the first five years after liver transplantation [9]. Furthermore, they recognized the importance of the presence or absence of chronic hepatitis C infection, both among the alcoholic and non-alcoholic patients alike. They found that among anti-hepatitis C negative alcoholic patients, relapse to heavy alcohol use was associated with steatosis and pericellular fibrosis in serial biopsies. These data suggest that early histological features of alcoholic liver disease are recognizable in the allograft. How these features develop or regress under the influence of treatment for alcoholism will be important to know in the future.
When analyzed according to hepatitis C status irrespective of alcohol use, their data were similar to those in the Mayo study; portal tract inflammation, portal and perivenular fibrosis were all more prevalent in HCV-infected recipients. Inevitably, given the number of variables (three degrees of alcohol use, chronic viral infection, and the slow progression of effects) Dr Burra's report should be considered pilot data. For example, the capacity to determine an interaction between hepatitis C and significant alcohol use was curtailed by having one person only in the chronic hepatitis C positive, heavy drinking group. Future studies should be directed to expanding the data in these at risk groups. This will probably require a multicenter approach, with prospective data gathering including the careful assessment of alcohol use as demonstrated in the present paper, and more extensive analysis of virological status.
Although these data must be interpreted with caution on account of small numbers, they show the potential for serial liver biopsies to elucidate important pathologic interactions among patients with liver transplants. I predict that future studies of long-term management of liver transplant recipients will focus on the principal causes of morbidity and late mortality, such as recurrence of the original disorder, the interactions of cardiovascular disease, hypertension, renal failure and hyperlipidemia, and recurrent or new-onset malignancy [10], [11]. It appears that the clinical course of some processes, such as hepatitis C-induced fibrosis, may be truncated in liver transplant recipients with progression from transplantation to significant allograft damage in months or years rather than years or decades as seen in the native liver [12]. Serial inspection of liver biopsies from stable transplant recipients with chronic hepatitis C, alcoholism or both offers the prospect of understanding the mechanisms of liver damage, repair and fibrogenesis through observing the sequence of changes prior to the onset of significant liver damage. The studies of Maor-Kindler and of Burra are a useful contribution to this growing literature and should encourage careful observational research projects using serial transplant liver biopsies in the future.
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PII: S0168-8278(01)00070-8
© 2001 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
