Fifty years of impact on liver pathology: a history of the Gnomes

Professional societies play a major role in medicine and science. The societies tend to be large with well-developed administrative structures. An additional model, however, is based on small groups of experts who meet regularly in an egalitarian model in order to discuss disease-specific scientific and medical problems. In order to illustrate the effectiveness of this model, the history and practices are examined of a long-standing successful example, the International Liver Pathology Group, better known as the Gnomes. The history shows that groups such as the Gnomes offer a number of important benefits not available in larger societies and nurturing such groups advances science and medicine in meaningful ways. The success of the Gnomes’ approach provides a road map for future small scientific groups. Electronic supplementary material The online version of this article (10.1007/s00428-020-02879-5) contains supplementary material, which is available to authorized users.


Introduction
Professional societies play a major role in shaping concepts, prioritizing academic pursuits, and providing expert guidance for clinical management challenges in patient care. Professional societies in most settings tend to be large in order to maximize impact. They have permanent bureaucratic structures to help them operate consistently and effectively, including official bylaws and standard operating procedures that outline committee structure and committee interactions, with a President and Executive Committee, and frequently a professional manager overseeing the entire operation.
An additional model, however, is based on small groups of experts who meet regularly in an egalitarian model without formal structure in order to discuss disease-specific scientific and medical problems. Of course, this model is not intended to replace or compete with the roles of traditional professional societies, but this model is nimble and flexible and can have a great impact on medicine and science. In order to illustrate this model, the history of a notable example is studied: the International Liver Pathology Group that in 2018 celebrated its 50th anniversary.

Origin and development of the Gnomes
The International Liver Pathology Group, better known as the Gnomes, emerged spontaneously in 1967 when a group of expert hepatologists and liver pathologists met to take on one of the most pressing problems of the day-how should chronic hepatitis be conceptualized, and what terms should be used to capture the various injury patterns seen on liver biopsy? This problem emerged because of the rapid spread during the 1950s and 1960s of the then new technique of using needle biopsies for the diagnosis and management of patients with liver disease. It was clear to pathologists and hepatologists that there were different patterns of hepatic injury, but the different patterns and their significance were confusing, at one point leading to at least 40 different terms in use for chronic hepatitis in the medical literature [1].
This issue was tackled in 1966 by the leadership of the newly formed European Association for the Study of the Liver (EASL) at the first annual meeting in Marburg, Germany. The EASL President, Gustav-Adolf Martini, and the Secretary, Jan De Groote (hepatologist and one of the founding members of the Gnomes from Leuven, Belgium), recognized the need for consensus on terminology for hepatitis injury patterns, so that uniform terminology would be used in the literature and permit fuller and more rapid progress in understanding inflammation of the liver [2]. To address this issue, it was decided to organize a session on this topic for the 2nd annual meeting of EASL, which was to be held in Gothenburg, Sweden, in 1967. Two German pathologists, Peter Gedigk from Bonn and Gerhard Korb from Weiden, were asked to host a slide seminar on this topic; both became founding members of the Gnomes [2]. Hans Popper, an Austrian-born liver pathologist working in New York, USA, had also been invited, but was unable to attend [2]. The session was attended by at least fifty individuals interested in hepatitis. The session was intense, stimulating, and so rewarding that at the suggestion of Jan De Groote a dozen attendees decided to skip the rest of the EASL meeting and continue their discussion on the terminology of hepatitis [3,4]. They realized they would need more time than this single meeting afforded, so they decided to take their preliminary consensus classification of hepatitis terminology and apply it to a group of circulated slides, and then to meet again. This next meeting, which took place on July 3-5, 1968, at the University of Zürich, Switzerland, is generally considered to be the first meeting and the official birth of the Gnomes, though at this point the group was known as the "European Liver Pathology Group" and had not acquired the moniker of Gnomes.
The Zürich meeting was hosted by Martin Schmid, another founding member of the Gnomes, and was sponsored in part by Hoffman-La Roche & Company [5]. The paper that resulted from the Zürich meeting is titled "A classification of chronic hepatitis" and summarized the new consensus classification of hepatitis developed by the nascent group soon to become known as the Gnomes. At the end of each day of this first meeting, Peter Scheuer (one of the founding members) typed up a summary of the day's discussion on a borrowed typewriter. As the only fluent English speaker, he became the de facto scribe and the meeting summaries formed the basis for the group's first paper [5]. The paper was quickly published in The Lancet in the fall of 1968. The classification system proposed in the paper attempted to identify patterns of hepatitis that were more likely to progress to cirrhosis (chronic aggressive hepatitis) versus those that were thought to be more indolent (chronic persistent hepatitis). This classification system built upon the earlier work of Valeer Desmet [3], which in turn was built on the 1966 publication of Martin Schmid [6], was an important early step in understanding chronic hepatitis and helped lay the foundation for modern understandings of inflammatory liver diseases. The basic dichotomy of chronic aggressive hepatitis versus chronic persistent hepatitis is no longer in use, but the core notion of the importance of "piecemeal necrosis" (now called interface activity) remains relevant to this day.
Following the Zürich meeting, this consensus paper was presented at the 1968 World Congress of Gastroenterology in Prague and subsequently at Karlovy Vary, Czech Republic, for the 1968 meeting of the International Association for the Study of the Liver (IASL) [3,4]. The president of IASL, Dame Sheila Sherlock, listened with interest but commented later at the meeting banquet, with some disapproval, that the authors were like the "Gnomes of Zürich," exercising undue influence on the field of liver disease and on the histological terminology of hepatitis [4].
The term Gnomes of Zürich referred to a popular notion that a small secretive group of elect bankers in Zürich had an undue influence on the world's financial systems. When the term Gnomes was first used by Sheila Sherlock, it was thus intended to be disparaging. The term, however, was gradually adopted by the group, with a bit of humor and as a badge of honor, being more convenient than the official name European Liver Pathology Group (1968Group ( -1978 or the more expansive name International Liver Pathology Group, which was adopted in 1979 when Kamal Ishak joined the group as the first non-European. In publications, the authorship byline was often listed simply as "International Group." While the more formal name International Liver Pathology Group is still occasionally used, by and large members refer to the group as the Gnomes. Other key events in the history of the Gnomes are listed in Table 1.

Members
There were nine founding members of the Gnomes ( Table 2). Three of the founding members (De Groote, Thaler, and Schmid) were hepatologists and the rest were pathologists [5]. The group was expanded over the next several years to 11 members and ( Fig. 1) held steady at between 11 and 14 members (Fig. 2). This number was felt to be optimal, providing enough members to capture a wide breadth of expertise, but numbers that could still easily meet in a modest-sized room and allow all members to speak freely and informally [8]. New members are inducted when members are no longer able to circulate slides [2] because of retirement, health considerations, scheduling issues, etc. These "emeriti" Gnomes are always welcome to continue attending the meeting and otherwise fully participate.
To date, there have been 36 Gnomes. All members were European until Kamal Ishak was inducted into membership in 1979 (Table 2). Technically, Hans Popper had joined in 1970 as an American, but he was considered to be European, and not American, by the members of the Gnomes [4]. The first Canadian joined in 1986 (James Phillips) and the first Australian in 2008 (Andrew Clouston). The first woman Gnome was Amelia Baptista from Lisbon, Portugal, who joined the Gnomes in 1976 (Fig. 1).
When new members are needed, names of candidates are proposed by any active member and discussed by the entire group, with a final decision put to a vote. Criteria for membership are equally weighted towards scientific interest, diagnostic or clinical expertise, collegiality, and friendship [4]. Nonetheless, all candidates are anticipated to be academic leaders in the field of liver disease/liver pathology. For example, the 14 members attending the 2018 meeting in Athens, Greece-the 50th year anniversary meeting ( . In addition, at the time of the 50th year anniversary meeting, they were editors or sole authors on thirteen books on liver pathology, including the seminal MacSween's Pathology of the Liver and the volume on Liver Tumors published by the AFIP [9][10][11][12][13][14][15][16][17][18][19][20][21]. Finally, current Gnomes members have been or are President or Executive Officers in all of the major International, European, US, Canadian, and Australian professional societies dedicated to pathology and liver pathology, as well as broader liver-focused groups such as the Canadian Association for the Study of the Liver (CASL) and the Austrian Academy of Sciences.
Over the years, the Gnomes have become aware of the critical shortage of pathologists in developing countries. The 2012 meeting, hosted by Franesco Callea, was held in Tanzania to support his ongoing efforts to provide pathology training at the Catholic University of Health and Allied Sciences -Bugando, Mwanza [22].

Gnomes' modus operandi
The group originally considered becoming a subcommittee of the EASL, but the members felt there were significant benefits to remaining an independent organization [4]. The group also decided to adopt an egalitarian structure, with no president, no secretary, and no bylaws [4]. Nonetheless, general customs and norms developed over the years for running the meetings (Supplementary material -Appendix). The meeting locations are chosen by the host, often being in the city of the host's hospital or academic department, and also at nearby resorts. The topics have varied, with most topics focused on medical liver diseases ( Table 3). The topics have been wide ranging, covering almost all aspects of medical and tumor liver pathology. The official red Gnomes hat was created by the mother of a medical student who was working with Peter Scheuer at the time [2,7]. The student persuaded his mother to make a hat suitable for a master gnome 2012 First meeting and Liver Symposium in Africa, held in Mwanza, Tanzania, hosted by Francesco Callea 2013 First meeting in Australia, held in Noosa, hosted by Andrew Clouston 2018 50th anniversary meeting held in Athens, Greece, hosted by Dina Tiniakos

Gnomes' scholarly contributions
One of the key missions of the Gnomes is to publish position/ nomenclature/review articles to help advance the scientific understanding of liver disease [2]. To this end, there has been a regular production of Gnomes' papers, totaling 12 at the time of the 50th year anniversary meeting in 2018 (Table 4). These papers have been widely cited, with the two most highly cited papers focusing on classification of hepatitis. The first Gnomes' paper "A classification of chronic hepatitis" [5] has been cited 1016 times, while the most highly cited paper was published in 1995 and has 4747 citations: "Histological grading and staging of chronic hepatitis" [29].

Organizational structures that contribute to success
Fifty years is a long time for a small group to survive, let alone thrive-why has the Gnomes been successful and lasted so long? Peter Scheuer emphasized the deep satisfaction of sharing cases with other skilled pathologists, scientists, and clinicians who share a passion for liver disease [2], as did Valeer Desmet [4]. Professors Scheuer, Desmet, and Bianchi all highlighted the importance of openly sharing ideas, questions, and knowledge without fear of embarrassment [4,7,8].
In fact, Leonardo Bianchi explicitly noted that the egalitarian organization does not tolerate hierarchy in determining primacy of ideas during discussions [8] or in determining group direction ( Figs. 1 and 2).
The notion of group fit comes through as a key element important to the health of the Gnomes [2,4]. This makes sense because the social and intellectual fabric of small groups like the Gnomes can be easily torn if a member is disrespectful, does not fully participate, or is otherwise unable to integrate into the group.
A third key element noted by Valeer Desmet is the ability to organize the group's efforts on a regular basis into meaningful   contributions to the scientific literature [4]. All of the Gnomes are committed to academic endeavors, and it seems natural and entirely fitting that this aspect of Gnome membership would be highly valued. Finally, the seamless integration of the Gnome partners and other family members into the social activities of the evenings and weekends brings to the Gnomes a true sense of community (Fig. 2).. Members get to know dimensions of each other not normally visible from typical academic meetings through shared social events, dinners, and other events. These informal environments promote trust, respect, and understanding.

Central role of histomorphology
Leonardo Bianchi emphasized the importance of pre-meeting circulated slides and pre-meeting submission of diagnoses as a key element of the Gnomes [8]. Based on a single  hematoxylin and eosin (H&E) slide, one unstained slide, and limited history, Gnomes members are asked to provide a diagnosis and limited differential. This unique approach requires each Gnome to commit to a diagnosis beforehand, allowing unbiased assessment for areas of consensus and areas of disagreement. In addition, the careful examination of the H&E-stained slide at these meetings has led to the detection and interpretation of previously undescribed structural and cellular alterations. The Gnomes not only fully embrace modern approaches such as molecular pathology, but also understand the continued value of careful morphological studies. Examples of observations made at Gnomes meetings and subsequently described in follow-up studies include the strong association of calcification within alpha-1-antitrypsin globules with the Mmalton variant [25], the visualization of lipid droplets within eosinophilic inclusions of fibrinogen, corresponding to apo-beta-lipoproteins [32], and histological changes in fibrinogen storage disease of hypofibrinogenemia and hypo-apo-beta-lipoprotein [33].
The Gnomes' slide sets are also very important as tools for educational training, including places or countries where H&E is the only available stain. In the last few years, some of the Gnomes have submitted scanned digital slides instead of glass slides, which also serve as an important educational tool, though the relative advantages and shortcomings of their use are still being explored.
At the end of the meeting, there also are opportunities for members to present their personal ongoing research. The opportunity to fully and openly discuss early ideas and data has been important in the process of refining many new ideas. There is a well-respected honor code that allows presentation of these initial ideas and early study results, without concern for other members absconding with them. These scientific topics incorporate and extend classical morphology using experimental models, molecular techniques, and biochemical methods, in order to better understand the basic principles of the disease and its morphological patterns. As one example, early work on the keratin nature of Mallory-Denk bodies was presented by Helmut Denk to the Gnomes, leading to vigorous and fruitful discussion by the group.

Other examples of the small group model
The core elements of the Gnomes model have been replicated by another group of liver pathologists, founded in 1990 and called the Elves, assisted by Peter Scheuer, one of the founding Gnomes members. Their formal name "The International Liver Pathology Study Group" is easily confused with the formal name of the Gnomes (International Liver Pathology Group), so both groups generally use their more informal but distinctive names. The Elves have enjoyed great success and their history and accomplishments were recently reviewed [34].

The future of the Gnomes
The Gnomes have consistently contributed to liver pathology for 50 years, but the future depends on the efforts of current members to keep it relevant, healthy, and productive. This depends on wise choices when selecting new members and on a rigorous and vigorous pursuit of the fundamental goal of the Gnomes: to improve the understanding of liver disease by tackling important issues in patterns of liver disease and in terminology.
For the first 50 years, the Gnomes focused their efforts on the histomorphologic patterns of disease. These activities remain important but now have to be more fully interwoven with the advances in the treatments for liver disease and improvements in non-invasive methods for diagnosing liver disease, assessing disease activity, assessing fibrosis, and integrating molecular findings into patient care. Starting about 10 years ago, the changes in treatment of liver disease have been rapid and sometimes stunning, with hepatitis C being a good example, in which rapid changes in the treatment and in non-invasive methods of assessing fibrosis have eliminated most of the clinical need for liver biopsy. These improvements in patient care are celebrated by all, especially Gnomes members.
Antipathy towards the value of liver pathology, however, is spreading among some clinicians, who express doubts about its usefulness in diagnosing and managing liver disease. The reasons for this are complex, but in part include the reduced exposure and understanding of liver pathology by newly trained physicians, who often receive considerably less training on normal histology and histopathology during medical school than formerly. In addition, there is a natural revision of diagnostic and treatment algorithms as new technology improves patient care. Refining the best fit for invasive and non-invasive methods in patient care takes time. Nonetheless, in all areas in which liver pathology can improve patient care, the Gnomes are committed to vigorously advancing the science of liver pathology interpretation.
The Gnomes experience indicates that small, agile professional groups can play an important role in medicine. These, and others like it, offer a number of specific benefits not available in larger specialty societies. We believe that nurturing such groups advances science and medicine in important, meaningful ways. The documentation of the Gnomes approach can provide a road map for the formation of future groups with a specific scientific focus.
Author contributions MT, VD, and DGT drafted the manuscript. All authors made substantial contributions to the conception of the work, revised the manuscript critically for important intellectual content, and approved the version to be published.

Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
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