From 1990 to present, 14 liver pathologists and 2 clinical hepatologists from 9 countries have met annually to hold thematic 2.5-day meetings centered on case-based discussion. The goal of these meetings has been to identify gaps in knowledge in our field and fuel scholarly effort to address these gaps. The founding principles were worldwide representation, good representation of women, compatibility of participants, commitment to stable membership and regular attendance, mutual education and friendship, and free exchange of ideas. A summary report of the 2.5-day meeting constituted an enduring document that captured the free flow of ideas discussed. These ideas were open to all participants for the pursuit of scholarship back at their home institutions. However, any idea borne out of an Elves meeting merits open invitation for other Elves to participate in, using established standards for meaningful coauthorship. Over 26 consecutive meetings (1990-2015), themes covered the breadth of liver pathology. With retirement of 2 individuals, resignation of 3, and death of 1, six newmembers were nominated and voted intomembership. Over these same 26 years, active members published 2025 articles indexed in PubMEd Central under the topic "liver;'' 3% of these articles represented collaborations between members. This international group represents a successful model in a subspecialty of anatomic pathology for open exchange of ideas, mutual education, and generation of topicsworthy of scholarly investigation. Weconclude that a self-selected group of subspecialty pathologists can meet successfully over 26 years, maintain a high state of engagement through each annual meeting, self-renew as a result of retirement or resignation, and provide a creative stimulus for highly productive academic careers.

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field.

Plasma cells and their precursors were studied by electron microscopy in liver biopsies from 41 patients with acute viral or drug-induced hepatitis. Mature plasma cells showed the ultrastructural features of the reticular or lymphatic type. Blast cells of different types were also observed. Type 1 predominated in classical acute hepatitis, and appears to transform directly into mature plasma cells. Type 2 corresponds to the centroblast of lymphoid tissue. It was found in fully developed hepatitis, especially when necrosis was severe. Type 3 resembled the centrocyte of lymphoid organs; it was seen particularly in viral hepatitis, and only in severe cases with extensive necrosis. The type 4 plasmablast had the ultrastructural characteristics of a plasmacytoid T cell.

HepatologyVolume 38, Issue 6 p. 1356-1358 EditorialFree Access Liver biopsy size matters in chronic hepatitis: Bigger is better Peter J. Scheuer M.D., Corresponding Author Peter J. Scheuer M.D. [email protected] Department of Histopathology, Royal Free Hospital, London, UK47 Northway, London NW11 6PB, United Kingdom; fax: (44) 20 8455 4383===Search for more papers by this author Peter J. Scheuer M.D., Corresponding Author Peter J. Scheuer M.D. [email protected] Department of Histopathology, Royal Free Hospital, London, UK47 Northway, London NW11 6PB, United Kingdom; fax: (44) 20 8455 4383===Search for more papers by this author First published: 30 December 2003 https://doi.org/10.1016/j.hep.2003.10.010Citations: 65AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994; 20: 15–20. 10.1002/hep.1840200104 PubMedWeb of Science®Google Scholar 2 Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696–699. 10.1016/0168-8278(95)80226-6 CASPubMedWeb of Science®Google Scholar 3 Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol 2003; 39: 239–244. 10.1016/S0168-8278(03)00191-0 PubMedWeb of Science®Google Scholar 4 Manabe N, Chevallier M, Chossegros P, Causse X, Guerret S, Trépo C, Grimaud J-A. Interferon-alpha 2b therapy reduces liver fibrosis in chronic non-A, non-B hepatitis: a quantitative histological evaluation. 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Diagnosing fibrosis in hepatitis C: is the pendulum swinging from biopsy to blood tests? Hepatology 2003; 37: 972–974. 10.1053/jhep.2003.50223 PubMedWeb of Science®Google Scholar 16 Poynard T, McHutchison J, Manns M, Myers RP, Albrecht J. Biochemical surrogate markers of liver fibrosis and activity in a randomized trial of peginterferon alfa-2b and ribavirin. Hepatology 2003; 38: 481–492. 10.1053/jhep.2003.50319 CASPubMedWeb of Science®Google Scholar 17 Lagging LM, Westin J, Svensson E, Aires N, Dhillon AP, Lindh M, Westjal R, et al. Progression of fibrosis in untreated patients with hepatitis C virus infection. Liver 2002; 22: 136–144. 10.1034/j.1600-0676.2002.01623.x PubMedWeb of Science®Google Scholar 18 Pilette C, Rousselet MC, Bedossa P, Chappard D, Oberti F, Rifflet H, Maıga MY, et al. Histopathological evaluation of liver fibrosis: quantitative image analysis vs semi-quantitative scores. 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Scoring of histological changes on liver biopsy, with its two components of grading and staging, is a widely-used tool in chronic hepatitis. Over the past decade it has replaced the earlier classification of chronic hepatitis into chronic persistent, chronic active and chronic lobular forms [1De Groote J. Desmet V.J. Gedigk P. Korb G. Popper H. Poulsen H. et al.A classification of chronic hepatitis.Lancet. 1968; ii: 626-628Abstract Google Scholar, 2Popper H. Schaffner F. The vocabulary of chronic hepatitis.N Engl J Med. 1971; 284: 1154-1156Crossref PubMed Scopus (94) Google Scholar], a classification devised at a time when most examples of chronic hepatitis were of unknown aetiology. In 1994, two independent international working parties agreed that the 1968 classification was no longer appropriate [3Desmet V.J. Gerber M. Hoofnagle J.H. Manns M. Scheuer P.J. Classification of chronic hepatitis: diagnosis, grading and staging.Hepatology. 1994; 19: 1513-1520Crossref PubMed Scopus (2505) Google Scholar, 4Working PartyTerminology of chronic hepatitis, hepatic allograft rejection, and nodular lesions of the liver: summary of recommendations developed by an international working party, supported by the World Congresses of Gastroenterology. Los Angeles 1994.Am J Gastroenterol. 1994; 89: S177-S181PubMed Google Scholar]. Grading of necroinflammatory changes and staging of structural alterations were seen as important requirements of therapeutic trials and as a possible supplement to verbal descriptions in routine diagnostic practice [[3]Desmet V.J. Gerber M. Hoofnagle J.H. Manns M. Scheuer P.J. Classification of chronic hepatitis: diagnosis, grading and staging.Hepatology. 1994; 19: 1513-1520Crossref PubMed Scopus (2505) Google Scholar]. Several different scoring systems are now available, and the inter- and intra-observer variation of some of these has been investigated. In their study of 127 patients with chronic hepatitis reported in this issue, Rozario and Ramakrishna from India used two different scoring methods [[5]Rozario R, Ramakrishna B. Histopathological study of chronic hepatitis B and C: a comparison of two scoring systems. J Hepatol 2003; 38:223–229.Google Scholar]. One was the modification by Ishak et al. [[6]Ishak K. Baptista A. Bianchi L. Callea F. De Groote J. Gudat F. et al.Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699Abstract Full Text PDF PubMed Scopus (4056) Google Scholar] of the earlier Histology Activity Index [[7]Knodell R.G. Ishak K.G. Black W.C. Chen T.S. Craig R. Kaplowitz N. et al.Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis.Hepatology. 1981; 1: 431-435Crossref PubMed Scopus (3405) Google Scholar]. The other was the algorithm devised by the METAVIR group in France [[8]Bedossa P. Poynard T. The METAVIR cooperative study group. An algorithm for the grading of activity in chronic hepatitis C.Hepatology. 1996; 24: 289-293Crossref PubMed Google Scholar] together with a simple staging system for fibrosis and cirrhosis [9Bedossa P. Bioulac-Sage P. Callard P. Chevallier M. Degott C. Deugnier Y. et al.Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C.Hepatology. 1994; 20: 15-20Crossref PubMed Scopus (1803) Google Scholar, 10Poynard T. Bedossa P. Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C.Lancet. 1997; 349: 825-832Abstract Full Text Full Text PDF PubMed Scopus (2753) Google Scholar]. The aim of Rozario and Ramakrishna's study was to compare the two scoring methods and also to investigate the correlation between the necroinflammatory component of the Ishak score and serum transaminase levels. In keeping with previously published results, this correlation was poor. In order to facilitate comparison between the Ishak and METAVIR scoring systems, the Ishak necroinflammatory scores were grouped into four grades of severity – minimal, mild, moderate and severe. There was moderate agreement between the two scoring systems for necroinflammation, and excellent agreement for fibrosis and cirrhosis. Similar results were obtained when biopsies from the 82 patients with chronic hepatitis B and those from 45 patients with hepatitis C were separately assessed. The practicalities of scoring affect the accuracy of the results. The METAVIR group [[9]Bedossa P. Bioulac-Sage P. Callard P. Chevallier M. Degott C. Deugnier Y. et al.Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C.Hepatology. 1994; 20: 15-20Crossref PubMed Scopus (1803) Google Scholar] performed a careful study of intra- and interobserver variation and, as also noted by others [[11]Goldin R.D. Goldin J.G. Burt A.D. Dhillon P. Hubscher S. Wyatt J. et al.Intra-observer and inter-observer variation in the histopathological assessment of chronic viral hepatitis.J Hepatol. 1996; 25: 649-654Abstract Full Text PDF PubMed Scopus (135) Google Scholar], found that variation was greater for necroinflammatory features than for fibrosis and cirrhosis. They commented that while a single observer was sufficient for recognition of general pathological features of chronic hepatitis C, two observers were likely to obtain better results for numerical scoring. The two observers should examine the biopsy specimens together. Significantly, each feature was comprehensively discussed between all observers at the beginning of the study, and agreement reached on the definition and scoring of each feature. The present study was carried out in a similarly careful way, both authors examining all biopsies and determining scores by consensus. Rozario and Ramakrishna conclude that both scoring methods are appropriate for use in chronic hepatitis B and C, and that the choice of system can be left to the preferences of the clinician and pathologist. They further comment that in their experience of routinely scoring all liver biopsies in their institution, the Ishak system has proved user-friendly and comprehensive, providing a quantitative value that is well understood by clinicians. Not everyone will agree with the last comment. Are the results of scoring really quantitative? The numbers generated for each pathological feature do not represent measurements but categories. The numbers are essentially the result of subjective judgements made by pathologists, and hence inevitably influenced by the observers’ experience and bias. That is why the METAVIR group agreed on definitions and scoring for each feature at the beginning of their study. Experience shows that different observers acting independently may generate somewhat different scores for a given feature such as interface hepatitis or lobular inflammation. The raw numbers generated in different studies cannot therefore be legitimately amalgamated in a meta-analysis. Indeed, even the results obtained by a single observer at different times are subject to observer variation, suggesting that the results of routine scoring of diagnostic liver biopsies can be misleading. In this author's view routine scoring should only be carried out if clinician and pathologist agree that it is needed for a particular purpose, and then only under carefully controlled conditions. What is the best scoring system? There can be no general answer to this question. In order to choose the most appropriate system, the clinician and pathologist should first define the purpose of scoring for their particular needs. If the purpose of scoring is simply to stratify patients into those with mild, moderate or severe disease for purposes of management, then a simple system is likely to be adequate. Several are available [8Bedossa P. Poynard T. The METAVIR cooperative study group. An algorithm for the grading of activity in chronic hepatitis C.Hepatology. 1996; 24: 289-293Crossref PubMed Google Scholar, 12Batts K.P. Ludwig J. Chronic hepatitis. An update on terminology and reporting.Am J Surg Pathol. 1995; 19: 1409-1417Crossref PubMed Scopus (914) Google Scholar, 13Scheuer P.J. Classification of chronic viral hepatitis: a need for reassessment.J Hepatol. 1991; 13: 372-374Abstract Full Text PDF PubMed Scopus (1357) Google Scholar] and a new scoring system can if necessary be devised to suit the particular project. Simple systems have two advantages; they are easier and quicker to use, and observer error is likely to be relatively low [[11]Goldin R.D. Goldin J.G. Burt A.D. Dhillon P. Hubscher S. Wyatt J. et al.Intra-observer and inter-observer variation in the histopathological assessment of chronic viral hepatitis.J Hepatol. 1996; 25: 649-654Abstract Full Text PDF PubMed Scopus (135) Google Scholar]. On the other hand, if the purpose of scoring is to detect small differences in liver damage or fibrosis in a clinical trial, then a system with a substantial range of numbers and therefore sensitivity would be more appropriate. Because of the greater likelihood of observer variation inherent in more complex systems, all possible steps to reduce this to an acceptable level should be taken. These include use of two or more observers, agreement on criteria before scoring is undertaken, consensus on scores where observers do not agree, and consistency audit of a proportion of the scored slides to make sure that intra-observer variation is not excessive. Scoring should be carried out without knowledge of the clinical details of the individual patients. Scoring of different biopsies should as far as possible be done over a relatively short period of time in order to avoid fluctuation of criteria in the minds of the observers. When scores are generated in a clinical trial or research project, they need to be handled according to their subjective nature. There is a temptation, not always resisted, to assume that because the results are numbers, they can be manipulated in the same way as, for example, measurements of serum bilirubin or viral load. Statistical methods used must be designed for categorical rather than numerical data. Moreover, individual components of grading scores (e.g. interface hepatitis, lobular hepatitis, confluent necrosis and portal inflammation) should be individually analysed. The scales for each of these differ from the others, and they are not linear. Combining them into a total necroinflammatory score gives an approximate idea of the severity of a patient's hepatitis, but not of the nature of the histological lesions involved. In the case of staging, morphometry, the measurement of tissue components in histological sections, provides an alternative approach [[14]Scheuer P.J. Standish R.A. Dhillon A.P. Scoring of chronic hepatitis.Clin Liver Dis. 2002; 6: 335-347Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar]. Collagen is stained by an appropriate method such as Sirius red, and the area occupied by fibrous tissue per unit area determined with the help of appropriate computer software. Masseroli [[15]Masseroli M. Caballero T. O'Valle F. Del Moral R.M. Pérez-Milena A. Del Moral R.G. Automatic quantification of liver fibrosis: design and validation of a new image analysis method: comparison with semi-quantitative indexes of fibrosis.J Hepatol. 2000; 32: 453-464Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar] investigated the differences between morphometry and staging and concluded that the two techniques were complementary rather than in competition. Staging takes into account not only the amount of fibrous tissue but also the presence or absence of structural changes such as nodule formation. Indeed, as cirrhosis develops and nodules enlarge, the amount of fibrous tissue per unit area may actually decrease rather than increase. However, morphometry does offer objective measurement as opposed to the subjective categorisation inherent in staging, and can sometimes detect changes not evident from the latter [16Manabe N. Chevallier M. Chossegros P. Causse X. Guerret S. Trepo C. et al.Interferon-alpha 2b therapy reduces liver fibrosis in chronic non-A, non-B hepatitis: a quantitative histological evaluation.Hepatology. 1993; 18: 1344-1349Crossref PubMed Scopus (173) Google Scholar, 17Duchatelle V. Marcellin P. Giostra E. Bregeaud L. Pouteau M. Boyer N. et al.Changes in liver fibrosis at the end of alpha interferon therapy and 6–18 months later in patients with chronic hepatitis C: quantitative assessment by a morphometric method.J Hepatol. 1998; 29: 20-28Abstract Full Text PDF PubMed Scopus (70) Google Scholar]. One obvious advantage of staging over morphometry, on the other hand, is that it needs no special equipment and is usually less time-consuming. Yet another approach to the problem has been measurement of the markers of fibrogenesis alpha-smooth muscle actin and C-terminal procollagen α1 (III) propeptide [[18]Kweon Y.-O. Goodman Z.D. Dienstag J.L. Schiff E.R. Brown N.A. Burkhardt E. et al.Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B.J Hepatol. 2001; 35: 749-755Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. Given the need for accurate, reproducible and practicable markers of necroinflammation and fibrosis in chronic viral hepatitis, the search for better methods should continue. In the meantime grading and staging must be performed critically and with due attention to the need to minimise observer variation.

Grading of the severity of chronic hepatitis and staging of its structural consequences are widely used in clinical trials of therapy and in research. Simple and complex methods are available. Intra- and interobserver variation can be reduced but not eliminated, because grading and staging are essentially subjective. The data are categorical rather than numerical and must be treated accordingly. Morphometry of fibrous tissue offers a different approach to biopsy assessment.

The "Gnomes" are an international group of liver pathologists and clinicians interested in liver morphology. The group was founded 30 years ago in an attempt to clarify the confusing concepts of chronic hepatitis that were then prevalent. Its first slide circulation and meeting resulted in the 1968 classification of chronic hepatitis. Recognizing the potential fruitfulness of the group, the members continued to meet for 2 or 3 days each year to discuss a variety of topics. The group has published nine reports that include guidelines for pathologists on different aspects of liver disease. Its membership has changed over the years, but many of the founding members continue to take part in the annual discussions.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) share many clinical and pathologic features. Central to the symptoms and biochemical alterations of both conditions is a substantial loss of intrahepatic bile ducts, leading to interference with bile flow, This pathologic change may ultimately result in cirrhosis of the biliary type, In addition, however, biopsy specimens usually show an element of liver-cell destruction and associated inflammation, mainly interface hepatitis, This finding is more pronounced in PBC than in PSC but can lead in both diseases to features that resemble those of cirrhosis as a result of hepatitis virus infection. The resemblance often leads to diagnostic confusion, which is easily overcome by attention to the clinical, radiologic, serologic, and biochemical contest. Histologic staging of PBC and PSC has led to a greater appreciation of their evolution but is hampered in biopsy material by sampling error. Examination of explanted livers at transplantation has demonstrated a wide variation in the maturation of lesions in various parts of the organ.

The Gnomes were conceived in Gothenburg in 1967 at the second meeting of the European Association for the Study of the Liver (EASL) because of a need to regularise the then confused nomenclature of chronic hepatitis. A small group of interested hepatologists met and, after animated discussion, agreed to circulate slides of relevant liver biopsy specimens and to reconvene the following year. The second meeting in Zurich led to the publication of the classification of …

From the University Department of Histopathology, Royal Free Hospital School of Medicine, London, UK

1. General Considerations 2. Laboratory Techniques 3. Diagnostic Cytology 4. The Normal Liver 5. Examination of the Abnormal Biopsy 6. Biliary Disease 7. Acute Viral Hepatitis 8. Fatty Liver and Lesions in the Alcoholic 9. Drugs and Toxins 10. Chronic Hepatitis 11. Cirrhosis 12. Neoplasms and Nodules 13. Vascular Disorders 14. Childhood Liver Disease and Metabolic Disorders 15. Disturbances of Copper and Iron Metabolism 16. The Liver in Systematic Disease and Pregnancy 17. The Liver in Organ Transplantation 18. Electron Microscopy and Other Techniques

All 684 post-orthotopic liver transplantation (OLT) liver biopsies performed at the Royal Free Hospital (RFH) between 1988 and 1993, from 120 patients, were reviewed in order to try to define the relative importance of the histological features of immunosuppressionresponsive cellular rejection. Twenty histological features considered to be possible contributors to the diagnosis of cellular rejection were documented in a binary (presentlabsent) fashion. These features in 106 biopsy specimens obtained 1 to 8 days after OLT were analyzed using stepwise logistic discriminant analysis. All clinical and treatment records were reviewed, and each biopsy specimen was assigned to a diagnostic category depending on these records and follow-up information. Important determinants of the histological diagnosis of cellular rejection (which occurred in 84 of the 106 cases) were moderate/severe mixed portal inflammation, eosinophils, endotheliitis, and bile duct damage. When these all occurred together, the odds of rejection increased 3.6-fold. The original histological diagnosis was recorded, and each biopsy specimen showing cellular rejection was regraded according to the specific criteria of Snover et al., Demetris et al., and a novel RFH scoring system. The latter consists of evaluating portal inflammation, endotheliitis, eosinophils, and bile duct damage, each on a 0 to 3 scale (none, mild, moderate, or severe, respectively) and summation. The resulting cellular rejection score thus can range from 0 to 12. The agreement between the different scoring systems was analyzed using K statistics, and there was good concordance (K, 0.64 to 0.78), despite different histological criteria being used to derive each score. Each system showed a similar degree of sensitivity (87% to 96%). The specificity ranged from 59% to 77%. We conclude that the histological diagnosis of cellular rejection relies mainly on the previously described features of mixed portal inflammation, endotheliitis, eosinophils, and duct damage. There is scope for unification and simplification of the existing grading systems, which depend on differing criteria, and we suggest one such scheme.

T” histological subdivision of chronic hepatitis into chronic persistent and chronic active forms was first advocated nearly 30 years ago (1,2). The underlying purposes of this classification were first to clarify the use of the term chronic active hepatitis, and secondly to distinguish between mild disease, chronic persistent hepatitis, with a low potential for cirrhosis, and more aggressive forms which might lead to cirrhosis by the process of piecemeal necrosis. Chronic lobular hepatitis was added to the classification shortly afterwards (3) to indicate a predominantly lobular (acinar) lesion, and the term chronic septal hepatitis was introduced to describe scarring without piecemeal necrosis (4). The classification was widely adopted by clinicians and pathologists alike. There are several good reasons why this simple histological classification no longer meets the needs of hepatologists. Foremost is the rapid increase in understanding of hepatitis virus infection, the main cause of chronic hepatitis. In 1968, when the histological classification was published, the hepatitis B virus had only recently been discovered (5) and little was known about its replication and behaviour in chronic infections. The hepatitis A virus was discovered a few years later (6). Testing for antibodies to the most important non-A, non-B virus followed in 1989 and enabled hepatitis C infection to be identified (7,8). All histological forms and degrees of severity of chronic hepatitis are found in both hepatitis B and C, but they sometimes have quite different clinical and prognostic implications. To give an example, in patients with hepatitis B in a phase of low viral replication (HBeAg negative, anti-HBe positive, low serum HBV-DNA) the histological appearances are typically those of chronic persistent hepatitis. For these patients the risk of developing cirrhosis is low, though not en-

‘Armed Forces instifute of Pathology, Washington, USA, 2University of Lisbon. Lisbon, Portugal, -‘Hofstetten, Switzerland, 4Servizio di Anatomia e Istologia Patologica. Spedali Civili, Brescia, Italy, 5Department of Medicine, University of Leuven, Leaven, Belgium, 61nstitute for Pathology, University of Basel, Basel, Switzerland, 7Department of Pathology, University of Graz. Graz, Austria, 8Department of Pathology, University of Leuven, Leuven, Belgium. 9 Weiden, Germany, ‘ODepartment of Pathology, Western Infirmary, University of Glasgow, Glasgow, UK, “Department of Pathology, ~osp~talfor Sick Children, University of Toronto, Toronto, Canada, ~‘~nstitute of Liver Studies, King’s College Hospital, London, UK, 13Frederiksberg, Denmark, Is Watt, Switzerland, “Vienna, Austria

Acute acetaminophen hepatitis was produced in three groups of five rats given 1600 mg/kg by gavage. The protective effect of 16,16-dimethyl prostaglandin E2, 200 µg/kg administered subcutaneously 30 min later, was compared to the protective effect ofN-acetylcysteine 1 g/kg similarly administered. All animals were killed at 24 hr, and liver tissues were compared histologically to the damage found in acetaminophen-treated controls and untreated anatomic controls. Serum transaminase values at 24 hr exceeded 1000 units in the acetaminophen control group, averaged 658 units in the acetylcysteine treated group, and were near normal (75 units) in the prostaglandin treated group (P<0.02). Liver samples (1 cm3) were removed terminally at 24 hr. Liver damage was assessed without reference to precedent history. Histopathologically, damage was most severe in the acetaminophen control group, mainly in pericentral lobular zones. The prostaglandin-treated group showed considerably less damage, which was confined to the hepatic vein area. The acetylcysteine-treated group showed an intermediate degree of damage. We conclude that dmPGE2, given 30 min after ingestion of acetaminophen was found to be more effective in limiting liver damage than NAC in this rat model.