The road to developing clinical trials: The Barcelona Liver Unit's experience and the dedication to the dream

Authors


  • Potential conflict of interest: Nothing to report.

  • I would like to dedicate this article to the four most important women in my life: my wife Paula and my daughters Idoia, Claudia, and Estefania (†1978-1988).

Where there is no vision, the people disappear. —King Solomon, Proverbs

A few months ago I was approached by the editorial team of HEPATOLOGY to contribute a piece to the Master's section, and considering the others who have contributed previously, I was honored to be invited but also rather daunted by the idea. Rarely do we have time to reflect over a period of 40 years in such a chronological way, but in doing so it has made me realize how much the field of hepatology and research has changed, especially in Spain. Although this article is my personal perspective of the development of hepatology and the Liver Unit at Hospital Clinic in Barcelona, Spain, the road to creating the Unit was not a journey I undertook alone; I was accompanied in the effort by Miquel Bruguera, Josep Maria Bordas, Vicente Arroyo, Josep Maria Sanchez Tapias, and Josep Teres.

Abbreviations

EASL, European Association for the Study of the Liver; HRS, hepatorenal syndrome; ICU, intensive care unit; SBP, spontaneous bacterial peritonitis.

A Brief History1, 2

In the 1960s, the world of medicine was a very different place, and nowhere more so than in Spain. Our country was under a dictatorship and was poor, having paid the price of a long civil war that was followed by years of isolation in both economical and political terms (Fig. 1). As a result, money for public services was scarce, and the hospitals were not the highly equipped modern centers that were developing in other western European countries at the time. Hospital Clinic I Provincial (as it was then known) was a university hospital, the management of which was totally integrated into the University of Barcelona. Therefore, the 20 chairs within the medical school were in complete control and ran the hospital. Each chair created their own domain, and these included patient wards, operating theatres, and diagnostic laboratories and their staff. The physicians, who worked in the hospital, did so because they had been accepted by the chair to work for them on their wards, in their operating theatres, or in their outpatient clinics. There were no employment contracts with the hospital, and the young physicians did not get paid for their work. In order to receive a salary, one needed to be hired through the university in an academic position. These domains even overlapped in terms of medical specialities. This raises the question: Why were young graduates so eager to start their careers at Hospital Clinic? The answer was simple: we received further training in specialized areas of medicine in addition to the prestige of being able to say we were working at Hospital Clinic.

Figure 1.

1938. Photo taken at the time of the bombing of Barcelona. An ambulance is arriving at the hospital with paramilitary forces at the gates.

Collaboration and cooperation between the “domains” was unheard of; furthermore, the structures needed in order to initiate and perform research were not in place. As a result, research production was nonexistent, and the idea that a person should aim to become a physician/investigator was an anathema. As I have already mentioned, this was a time of dictatorship; however, Spain had not always been in this situation. At the turn of the previous century, the country was thriving with research and new discoveries. The pinnacle of this era was when Santiago Ramon y Cajal was awarded the Nobel Prize for Medicine in 1906 for his study of the brain, brain tissue, and neurons. His work laid the foundation for modern neuroscience. His legacy and achievements had a marked influence on several students—particularly Severo Ochoa, who went on to receive the Nobel Prize for Medicine in 1959 for the discovery of RNA when he was based in the United States. The careers of these eminent figures continued to influence future generations—myself included—but there was another physician turned investigator who, in some respects, had an even greater influence upon us, probably because he was Catalan: August Pi i Sunyer. Pi I Sunyer had graduated from the University of Barcelona School of Medicine. He spent his early years working as both a physician and as an investigator. He founded the Royal Academy for Medicine in Barcelona and the Institute of Physiology in the Medical School of the University of Barcelona in the 1920s. In many respects, his working life was very similar to that of a physician/scientist today, as he spent much of his time delivering invited lectures in Universities both in Spain and worldwide. Due to the political environment, he left Spain in 1939, but continued his work in Venezuela and then in Mexico, where he lived in exile until his death in 1965. The influence of these great physicians and scientists upon us young men leaving university was immense, and I for one was keen to emulate and follow in their footsteps. Their scholarly trajectory showed that research and clinical practice was possible, although by what means was still not quite clear. Years later, in 1996, we founded and inaugurated the first translational research institute here in Spain: Institut de Investigacións Biomedicas August Pi I Sunyer (more commonly known as IDIBAPS).

So, after having come from a fertile land of research in the first quarter of the century, by the mid-1960s we were in a desert. We were living and practicing medicine in western Europe, but as a third-world country. I knew I wanted to be a physician, but I also wanted to investigate and “discover.” The problem was, how? Besides which, there was a more pressing issue: To what field of medicine was I going to dedicate my life? The year was 1962, and the initial Spanish studies on the artificial kidney were appearing, thus making nephrology an attractive choice. However, the same idea occurred to half the people also graduating, and suddenly nephrology was a highly competitive field. For this reason, I decided that the liver might be interesting. At the time, there were the several publications by Hans Popper, Jacques Caroli, and the great Shelia Sherlock, but in comparison to nephrology and other specialties, the field had hardly been explored, thus making it attractive. On graduation both Josep Teres and I were fortunate enough to be taken on as interns in the Department of Internal Medicine headed by the Chair, Professor Juan Gibert Queralto. I was assigned to one of the two women's wards, and Josep Teres was placed on the men's ward. We did not have work contracts with the hospital as there were none, but the Ministry for Internal Affairs paid us for any visits we did in the outpatient clinic. A couple of years later, we were joined by the other two founding members of the Liver Unit, Miquel Bruguera and Josep Maria Bordas.

Having no contract meant I had no ties. I applied for and was awarded a grant from the French Government, which enabled me to continue with my training. In 1964, I left Barcelona and headed for the world renowned Hôpital Saint Antoine in Paris to study under the master, Jacques Caroli. I suppose this is where the seed for the Barcelona Liver Unit began to germinate. The year I spent in Paris had a formidable effect on me. I learned new techniques and more about liver diseases than I had ever imagined; in addition, I saw an institutional structure very different from the one I had known. The hospital was divided into specialities and had integrated into this structure clinical research and basic science labs, all the requisites needed for research production. This model would later become the basis for our unit. Not only that, it was Paris in the swinging sixties!

On my return to Barcelona, I accepted a position to work for Professor Gibert Queraltó in the hospital, though my position was contracted through the University giving me a step onto the first rung of the ladder of an academic career. In 1967, I defended my doctoral thesis, “The Clearance of Bromosulphtalein in Patients with Liver Disease,” at the University of Barcelona based on my work in Paris under Jacques Caroli. The importance of having spent this year in Paris is difficult to emphasize, but suffice it to say its influence played a role in the decisions of both Miquel Bruguera and Josep Maria Bordas to pack their bags and head to the mecca of Saint Antoine and Jacques Caroli in 1967.

In 1968, we attended our first international conference on hepatology in Czechoslovakia. We met “the” hepatologists of the time: Hans Popper, Shelia Sherlock, Roger Williams, Jean Pierre Benhamou, and Neil McIntyre. This confirmed to us that our future lay in the field of clinical investigation of liver diseases. The Liver Unit started unofficially on a February night in 1969 at my mother's family home in the Catalan village of Montferri, Tarragona (Fig. 2). At this point, we had two new members, Vicente Arroyo and Josep Maria Sanchez Tapias, both of whom were newly graduated doctors working in internal medicine. The founding cornerstones of the Liver Unit were based on our common interest in clinical investigation. The majority of patients we saw had cirrhosis, so it seemed logical to concentrate our efforts on two areas: cirrhosis and its complications, and hepatitis. Based on my experience in Saint Antoine, I realized that specialization was important. With that in mind, Vicente Arroyo and myself dedicated our time to ascites, Miquel Bruguera and Josep Maria Sanchez Tapias concentrated on hepatitis, and Josep Maria Bordas focused on developing the techniques of laparoscopy and endoscopy. In addition, the training periods abroad undertaken by Vicente Arroyo and Chema Sanchez Tapias in the United Kingdom proved to be extremely valuable for our new unit. Vicente worked in the lab with Roger Williams and Chema with Shelia Sherlock. Their experiences propelled us forward in terms of what we wanted to achieve. The field was virgin territory in Spain; therefore, it is hard to highlight the pivotal moments and epiphanies, as looking back there seem to have been so many. However, in terms of the development of our unit and the field of hepatology in Spain, one of the decisive moments has to be the short stay of Miquel Bruguera with Peter Scheuer in London. Peter Scheuer was a renowned pathologist at the time, and Miquel became one of his disciples. Each day before reviewing the liver biopsies, he allowed him to study them and offer his opinion; Miquel had to survive the scrutiny of his master each day. On his return to the Liver Unit, he took the lead and used liver biopsy as a unique method of diagnosis, which was not the usual practice at the time. An added string to the bow in the development of the diagnostic techniques we were implementing was the introduction of ultrasonography. A young female doctor by the name of Concepción Bru, who was working with Josep Maria Bordas, first went to Marseille to learn the technique in 1979, and then on her return dedicated her time to use the technique for the evaluation of liver diseases. A department specifically dedicated to using ultrasonography was started in 1981 under the umbrella of radiology. From the first moment that Conxita started working with us in the early 1970s, she has officially never been a member of the Liver Unit; however, her role has been important, and she is a fine example of how interdepartmental cooperation has been decisive in the Liver Unit's development over the years. We started to write and publish many papers, although the first publications were descriptive pathophysiological studies.

Figure 2.

Montferri, 1968. The founders of the Liver Unit (left to right): Josep Maria Sanchez Tapias, Vicente Arroyo, Benet Nomdedeu, Juan Rodés, Josep Maria Bordas, Miquel Angel Gasull, Miquel Bruguera.

I should mention at this point that from an institutional perspective, the structure of the hospital had not changed. In order to carry out our research, we had to convince Professor Gibert Queralto to give us a small corner within his internal medicine department. We were given a place to process liver biopsies and store all the data we had collected from the patients with liver diseases that we saw. In 1970, we were officially recognized by the chairs and the hospital and were given the name Servicio de Hepatologia. This was not only a step forward for our organizational structure, but also had an enormous benefit for the patients, as they were now able to organize a visit with a hepatologist. We were given more space so we could have our offices, we had a ward for our patients, and we had a small library that doubled as a meeting room so we could hold regular clinical sessions. These clinical sessions were held in the mornings, and whoever was the last to arrive had to buy breakfast for all the others—which was enough motivation to instill punctuality and regular attendance! However, change was in the wind, and many of the young physicians working at Hospital Clinic began to manifest their dissatisfaction with the working conditions by not turning up for work; without them, the hospital was unable to function. This matter was put to a vote, the result being that the first hospital contract to a physician was given out in 1971 (Fig. 3). Over the subsequent 2 to 3 years, a management hierarchy was brought into the Hospital, and the empirical structure of the chairs faded out. This new organizational structure was similar to that of other large European hospitals. These changes within the hospital were rather fortuitous, as it meant that Vicente Arroyo was able to fulfill his aim to start a research lab after returning from London.

Figure 3.

1972. Photo of Juan Rodés (second from left) voting while surrounded by the administrators of the hospital.

Another defining point in the Liver Unit's history was the creation of the intensive care unit (ICU), which was in fact the first ICU in the hospital. This was due to Josep Teres' interest in managing patients with liver failure and gastrointestinal bleeding. The ICU was directly based on what he had learned during his training period with Jean Pierre Benhamou in Hŏpital Beaujon in Paris. The first beds became available in 1971. We were beginning to thrive, and more young physicians were keen to join us. One of the conditions we had initially decided upon was to make it imperative for the new members to spend a period of training abroad to broaden their knowledge, and on their return their experiences would benefit the unit as a whole, a philosophy which is still current today. We, as founding fathers, went abroad within Europe; however, change was afoot, and Jaime Bosch was the first to go further afield to work with Roberto Groszmann at Yale University. Upon his return, the Hepatic Hemodynamic laboratory was born. The other members and their destinations are shown in Table 1.

Table 1. Barcelona Liver Unit Members–Overseas Training
MemberYear of IncorporationTraining
InstitutionYear(s)Mentor(s)
Juan Rodés1967Hôpital Saint-Antoine, Paris, France1964Jacques Caroli
Josep Maria Bordas1967Hôpital Saint-Antoine, Paris, France1967Jacques Caroli
Hôpital Edouard Herriot, Lyon, France1971J. Lebreque
Miquel Bruguera1967Hôpital Saint-Antoine, Paris, France1967Jacques Caroli
Royal Free Hospital, London, UK1973Peter J. Scheuer
Josep Teres1968Hôpital Beaujon, Paris, France1969Jean Pierre Benahmou
Vicente Arroyo1968King's College, London, UK1972-1974Roger Williams
Josep Maria Sanchez Tapias1968Royal Free Hospital, London, UK1975-1976Dame Shelia Sherlock
Jaime Bosch1975Yale University, New Haven, CT1980-1982Roberto Groszman
Juan Caballeria1979Alcohol Research and Treatment Center, Bronx VA Medical Center, Mount Sinai School of Medicine, New York, NY1986-1987Charles S. Lieber
Antoni Rimola1981University of Pittsburgh, Pittsburgh, PA1984David H. van Thiel
Albert Pares1984The Johns Hopkins Hospital, Baltimore, MD1991Esteban Mezey
Antoni Mas1985   
Jordi Bruix1985National Cancer Center de Tokyo, Tokyo, Japan1990Masatoshi Makuchi and Masamichi Kojiro
University of Washington, Seattle, WA1995-1997Nelson Fausto
Pere Ginès1988Department of Nephrology, University of Colorado, Denver, CO1992-1994Robert W. Schrier
Miquel Navasa1990Veteran's Hospital San Francisco, University of California, San Francisco, CA1995-1996Carl Grünfeld and Ken Feigold
Juan Carlos Garcia Pagan1994Biology Department. University of North Carolina, Charlottesville, VA1996-1997Mark G. Clemens
Xavier Forns2000Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institutes of Health, Bethesda, MD1996-1999 
2008-2009Robert H. Purcell
Angels Escorsell2001   
Ramon Bataller2004University of North Carolina, Chapel Hill, NC2002-2003David Brenner
Alberto Sanchez Fueyo2004Harvard University Medical School, Boston, MA2000-2004Terry B. Ström
Javier Fernandez2005   
Jordi Colmenero2010   
Juan Gonzalez Abraldes2011Yale University Liver Center, New Haven, CT2003-2004Roberto Groszman

By this point, we had plenty of patients, and funding for the studies was obtained by applying for competitive public grants, the first of which became available in the early 1970s. At this point, the pharmaceutical industry was not yet a source of funding (this first came about in the mid-1980s, which helped increase and widen our research fields).

Research Development and Clinical Trials

By the mid-1970s, we were established, and the hospital recognized that we were performing a vital role in clinical research despite some early misgivings. We were publishing papers, albeit very descriptive studies, until the second part of the 1970s, when we started to work on our first full important clinical trial, the results of which were published in Gastroenterology in 1983.3 This set us on the road to publishing more than 168 clinical trials by 2003, when I moved from being the Head of the Liver Unit to take over the role of Director of the Hospital.

The first clinical trial we performed that had a relatively important repercussion in clinical practice was a study designed to compare the efficacy of furosemide versus spironolactone in patients with nonazotemic cirrhosis with ascites.3 It was well established that loop diuretics were standard drugs for the treatment of ascites. Although pharmacologic studies indicated that the natriuretic potency of loop diuretics was much greater than that of distal diuretics, there were no studies comparing the efficacy of these drugs in cirrhosis. The purpose of the trial was to compare the efficacy of both drugs in nonazotemic patients with cirrhosis who have ascites. The diuretic effect of both drugs was related to the activity of the renin-aldosterone system. The conclusion of the study was that spironolactone was more effective than furosemide in patients with nonazotemic cirrhosis with ascites. These findings laid the groundwork for the current treatment of ascites.4

The second trial that was pivotal was the demonstration that somatostatin was effective for patients with variceal hemorrhage. We previously demonstrated that somatostatin reduced portal pressure in patients with cirrhosis.5 However, there was no controlled clinical trial that compared the efficacy of somatostatin versus vasopressin, the standard drug used in patients with acute variceal hemorrhage.6 For this purpose, patients with cirrhosis who had endoscopically proven active variceal bleeding were included. This study was the first to demonstrate that somatostatin was as effective as vasopressin in controlling variceal bleeding, but with a lower rate of complications. At present, somatostatin and its analogues are used as a first-line treatment for patients with cirrhosis and active variceal bleeding in many centers across the world.7

In the 1980s, we analyzed why paracentesis was forbidden as a treatment for patients with cirrhosis and tense ascites. At the time, we were unable to find any controlled clinical trial demonstrating this contention. Therefore, we designed a study to answer this dogma. We assessed whether paracentesis along with intravenous albumin could be considered as alternative therapy to diuretic treatment in patients with cirrhosis with large and tense ascites.8 Patients treated with diuretics developed complications such as renal failure, electrolyte disturbances, and hepatic encephalopathy. In addition, the duration of hospital stay was significantly lower in patients treated with paracentesis compared with those treated with diuretics. For the first time, these results clearly demonstrated that paracentesis along with intravenous albumin infusion was a fast, effective, and safe therapy for patients with large amounts of ascites. Later, in another controlled clinical trial, we were able to demonstrate that total paracentesis plus albumin infusion was also safe, indicating that these patients could be treated as outpatients.9 Current guidelines recommend this approach for those patients with large and tense ascites.4

In 1988, we demonstrated that patients with spontaneous bacterial peritonitis (SBP) (the majority due to aerobic gram negative bacteria due bacterial translocation) had a high risk of developing a new episode associated with high mortality within 1 year.10 Therefore, we designed a controlled clinical trial to determine whether norfloxacin could prevent the development of recurrence in those that recovered from an episode of SBP.11 We also demonstrated that oral norfloxacin produced a selective intestinal decontamination (elimination of aerobic gram-negative bacilli from the fecal flora without significant changes in other microorganisms). Patients with cirrhosis who have these characteristics were included in a multicenter, double-bind trial aimed at comparing long-term norfloxacin administration versus placebo in the prevention of SBP recurrence. The overall probability of SBP recurrence at 1 year of follow-up was 20% in the norfloxacin group and 68% in the placebo group. This led to the conclusion that oral norfloxacin was very effective in preventing recurrence of SBP. At present, the administration of norfloxacin is recommended in all patients with cirrhosis who have a prior episode of SBP in order to avoid its recurrence.4

In 1981, Lebrec et al.12 had demonstrated the propranolol reduced portal pressure in cirrhotic patients and prevented esophageal rebleeding. Pascal and Cales13 went on to demonstrate that propranolol was effective in preventing a first bleeding episode in cirrhotic patients. However, there was a need to confirm these results in a large cohort. In the late 1980s, together with the groups from New Haven and Boston, we organized a multicentric double-blind randomized control clinical trial to assess the effectiveness of propranolol for the primary prevention of variceal bleeding.14 Patients with cirrhosis who had hepatic venous pressure gradients greater than 12 mm Hg and with esophageal varices were randomly assigned to propranolol or placebo. The results demonstrated that propranolol effectively prevented the first variceal hemorrhage in patients with cirrhosis and large esophageal varices but did not improve survival. Since the publication of this paper, the vast majority of patients with cirrhosis who have high-risk varices are given propranolol as primary prophylaxis for prevent variceal bleeding. Current guidelines support this strategy.7

In patients with cirrhosis and SBP, renal function frequently (≈30%) becomes impaired in spite of infection resolution with antibiotics. This impairment is probably related to a reduction in the effective arterial blood volume and is associated with a high mortality rate.15 We conducted a study to determine whether plasma volume expansion with intravenous albumin prevented renal dysfunction and reduced mortality in these patients.16 Patients with cirrhosis and SBP were randomly allocated to be treated with cefotaxime or cefotaxime and intravenous albumin infusion. This study demonstrated that patients with SBP should be treated with intravenous albumin infusion and antibiotics in order to reduce the development of renal failure and death. The result of this study changed the prognosis of these patients particularly those in the waiting list for liver transplantation. The possible benefit of albumin infusion may also be due, in addition, to plasma volume expansion, to its action on endothelial function that, in turn, may reduce arterial vasodilatation.17

In 1988, it was suggested that development of hepatorenal syndrome (HRS) was due to an intense splanchnic vasodilatation as a consequence of marked portal hypertension that eventually led to low blood pressure.18 This would produce an activation of vasoconstrictor systems in order to maintain arterial pressure within the normal or near normal values. However, the activation of these systems would develop an intense arterial renal vasoconstriction and consequently lead to the development of HRS.18 Thus, the administration of vasoconstrictors with an effect on the splanchinic circulation was an attractive target to treat this very severe complication of cirrhosis with high mortality rates. In a previous study, we had demonstrated that ornipressin, a vasopressin analog with a potent splanchnic vasoconstrictor action, was able to reverse HRS. However, its usefulness in clinical practice was limited by frequent ischemic complications. Therefore, we developed a pilot study to assess the efficacy of terlipressin, an analog of vasopressin with a low profile of side effects plus albumin in patients with HRS.19 The administration of terlipressin was associated with a marked reduction of serum creatinine. Reversal of HRS was observed in the majority of patients. There was, in addition, a remarkable improvement in circulatory function with an increase in mean arterial pressure and suppression of vasoactive hormones. No patient developed signs of intestinal, myocardial, or distal ischemia. The results of this study suggested that terlipressin along with albumin infusion reversed HRS.19 Since the publication of this paper, other clinical trials have confirmed this observation.20 Today, this therapy is considered a first-line approach and is recommended in all clinical guidelines. Furthermore, the use of terlipressin with albumin can improve renal function in patients awaiting liver transplantation and may allow them to reach liver transplantation with near normal renal function.

The last study that had an important influence in clinical practice during the period 1972-2003 was the use of arterial embolization or chemoembolization in patients with intractable hepatocellular carcinoma.21 Before this clinical trial, arterial embolization was widely used, but evidence of survival was lacking. Therefore, we performed a randomized controlled trial in patients with unresectable hepatocellular carcinoma not suitable for curative treatment. Patients were Child-Pugh class A or B and Okuda stage 1 or 2. We assessed the survival benefits of regularly repeated arterial embolization (gelatine sponge) or chemoembolization (gelatine sponge plus doxorubicin) compared with conservative treatment. The primary endpoint was survival. The trial was stopped when the ninth sequential inspection showed that chemoembolization had survival benefits compared with conservative treatment. At present, this therapy is widely implemented in such patients.22 During this whole period, there were many other important trials performed by the Liver Unit, but it is impossible to discuss all of them.

The Liver Unit's Research Web

In the 1980s, we began to develop our research areas due to the wider research interests of the newer generation of physicians who joined us. Antoni Rimola went to Pittsburgh to work in the Thomas Starzl Institute under the guidance of David Van Thiel, and on his return the liver transplant program was started. We performed our first transplantation in 1988. Since then, the Hospital Clinic has performed more than 1,650 liver transplantations and 70 living donor liver transplantations, making it the leading hospital for liver transplantation in Spain. Other areas that became increasingly important were liver cancer, bacterial infections in cirrhosis, alcoholic liver disease and nonalcoholic steatohepatitis. Jordi Bruix first went to work with Masatoshi Makuuchi and Masamichi Kojiro at the National Cancer Center in Tokyo, Juan Caballeria went to the United States to work with Charles S. Lieber in New York, Albert Pares joined Steve Mezzey's lab in Baltimore, and Miquel Navasa headed off to the University of California, San Francisco. All went to train in hepatology labs; the one person who differed in this sense was Pere Ginès, who went to work with the renowned nephrologist Robert Schrier in Denver (Fig. 4).

Figure 4.

1984. Newly incorporated doctors and fellows to the Liver Unit at the EASL Meeting in Berne, Switzerland (left to right): Pere Ginès, Faust Feu, Wladimiro Jimenez, Juan Caballeria, and Jordi Bruix.

In the early days, I had an extra interest in basic science and understood the concept of translational science before it became common usage. However, given our limited knowledge in laboratory techniques, it was not until 1982, when a young biologist named Wladimiro Jimenez came to work with us, that we performed our first experimental studies using rat models. The first paper we published was in HEPATOLOGY in 1985.23 In exactly the same mode as the rest, Wladimiro Jimenez also went overseas to complete his postdoctoral studies in the Renal Division of Brigham & Women's Hospital and Harvard in Boston in 1991. On his return, we convinced the hospital that a diagnostic lab was a necessary instrument for the development of research and improving patient management. Wladimiro became its head, and it was at this point that we could really begin to develop translational lines of research. This was the starting point of a fruitful interdisciplinary research collaboration that has developed over the years thanks to Joan Claria, Jose Carlos Fernandez Checa, Carmen Garcia Ruiz, and, more recently, Mercedes Fernandez and Manuel Morales.

The Name and Fame

Throughout the 1970s, we (all the members of the Liver Unit) worked hard to create a name for ourselves in the international field of hepatology, and it was during this period that we became known overseas as the Liver Unit, Barcelona—a name that has stuck to some extent despite the existence of other excellent liver units based in other hospitals in and around Barcelona. However, at the time, we were the only ones conducting research and publishing papers, and we were the only hospital that had a dedicated hepatology unit, so by default we were known as the Barcelona Liver Unit group. Obviously, over this 40-year period there have been other influences and factors that brought recognition to the unit, and none more so than the number of fellows from overseas who have undergone training with us; they have also contributed to this success. It has to be said that the relationship of the Hospital Clinic over the years with various important institutions throughout Latin America has been of great importance. This is largely thanks to the Liver Unit, who received their first fellow for further training in 1975: Flair Carrilho from São Paolo, Brazil. Ruben Terg, from Buenos Aires, Argentina, joined us soon afterward, as did Jorge Luis Poo from Mexico. Each one of these individuals has gone on to become an influential voice in the field of hepatology in their own country. Over the past 40 years, more than 1,000 physicians from all over Latin America and other corners of the world have passed through the Liver Unit, either for short-term specialized training or more long-term periods to perform research. The value and prestige of the liver unit is represented by many of the first generation fellows who have gone on to lead hepatology units in their institutions and are now in a position to send their young fellows to us for further training. This has helped to extend the network of the Liver Unit. There were two other people who were also implicated in this network development: Roberto Grozsmann and Andy Blei. Roberto had established himself in the United States, and Andy went to join him before moving to Chicago. With the language in common, we gravitated toward each other at congresses and meetings, and what started as professional relationships soon became close friendships. In the mid-1980s, we (Roberto Groszmann, Andy Blei, Marcos Rojkind, Jaime Bosch, Vicente Arroyo, and myself) formed a small association for Spanish-speaking hepatologists aimed at doctors from all over Latin America and Spain. Although this association lasted only 4 or 5 years, it helped build a network and encourage trainees from Latin America to receive training abroad (Fig. 5).

Figure 5.

1992. Photo taken at the meeting of the Spanish-speaking hepatologists in Yucatan, Mexico. Back row: Roberto Groszmann, Guadalupe Garcia Tsao, Jaime Bosch; front row: Vicente Arroyo, Juan Rodés, Andres Blei (with wives and partners).

The societies have also played an important role in the development of the Liver Unit, as we were able to establish professional relationships as well as personal friendships with many of its members. Obviously, the three most important have been the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver (EASL), and the International Association for the Study of the Liver. I joined the scientific committee of EASL in 1976. This started what became for me quite a long personal relationship with EASL as Shelia Sherlock asked Rudi Preisig and myself to join her as the first associate editors of the Journal of Hepatology in 1980-1984. Twenty years later, in 2000-2005, I was given the post of Editor-in-Chief. The success of the Barcelona editorial office was due to the hard work and support of Pere Ginès and Xavier Forns as well as all the associate editors at the time. Relationships with the different international societies have continued, and many younger members of the Liver Unit have gone on to be influential members of these societies driving the whole field of hepatology forward.

Post-2003

By the time I left the position of Head of the Liver Unit in 2003, it was divided into the major areas of liver diseases. These included hepatitis, cirrhosis, portal hypertension and variceal bleeding, liver fibrosis, liver transplantation, alcoholic liver disease, sepsis and spontaneous bacterial peritonitis in cirrhosis, cholestasis, and autoimmune liver diseases. Many of the members are internationally renowned physicians/scientists. However, at this point, I believe probably one of the most important members of the Liver Unit is Miquel Bruguera, as he has been an influential and prominent voice for our specialty in Spain. Through his perseverance and enormous intellectual capacity, over the years he has become the Spanish hepatologist of reference for any strange or rare liver disease. When he started studying the biopsies in Peter Scheuer's lab all those years ago, never would he (or I for that matter) have imagined that over a period of 40 years he would review more than 35,000 liver biopsies and give a diagnosis for each one. He is Spain's reference for cases of Wilson disease; he is the person we all consult when we are unsure about a case. In addition, he was the President of the Barcelona Colegio de Medicos (the official register for physicians) between 1994 and 2008, and the extent of his influence on the practice of medicine in our country is difficult to quantify.

The era of post-2003 has seen the Liver Unit publish even more state-of-the-art research papers that have changed the clinical practice of managing patients. Vicente Arroyo and Pere Ginès' research on terlipressin and renal failure,24, 25 Jordi Bruix and Josep Maria Llovet's contributions on the effects of sorafenib in liver cancer,26 Jaime Bosch and Juan Carlos Garcia Pagan's work in variceal bleeding and portal hypertension and transjugular intrahepatic portosystemic shunt,27 Josep Maria Sanchez Tapias and Xavier Forns' contributions on HCV,28 Miquel Navasa's work in bacterial infections, and of both he and Antoni Rimola in the development of liver transplantation, Albert Pares and his work on cholestasis and autoimmune hepatitis29, 30 and Juan Caballeria's work in the area of alcohol are all examples of the great experts we have in our unit. I have an enormous sense of pride when I see the teams of authors of many current guidelines for clinical practice and management in various different areas of hepatology and they include members of the Liver Unit, Hospital Clinic Barcelona, a point probably difficult to match by any other center in the world. I suppose it could be said that we as founding members have achieved our initial objective. When I left the Liver Unit in 2003, Vicente Arroyo took over, and now the reins are in the hands of Pere Ginès, who is taking it forward in the 21st century. Since 2003, the Liver Unit has continued to grow and has published 27 clinical trials.

Writing this article has made me reflect on the journey we have made and how far we have come; however, as with all great achievements and adventures, we were not alone. We were accompanied along the way by many people—first and foremost our wives and families, who have supported us every step of the way. Much of what we achieved has also been because of the team of nurses and the administrative staff who have worked with us; I feel it would be wrong not to mention some of them by name, as they have also played an important part in the development of the Liver Unit: Magda Ferrer, the first nursing supervisor in the ICU; Anna Padro, who has worked with the transplant patients from the beginning; Raquel Cela, our research nurse; and Miquel Sanz, who is the current supervisor in the ICU. We have been very fortunate to have had very loyal administrative support, first from Vicky Llagostera, followed by Monica Masllorens (who worked with us for more than 25 years before sadly succumbing to a brain tumor), and Nicki van Berckel, who joined us to work on the Journal of Hepatology back in 2000 and has never left! Without her help and support, this article would never have made it to print.

Finally, as this paper was being written, our very close colleague Joan Manuel Salmeron passed away at the young age of 51. He started out with us as a hepatologist and went on to head the emergency department of the hospital. May he rest in peace.

Is there a motto to be found or a philosophy to be taken from this journey? Probably not. However, I do believe that we reached our goal because of our desire to dream, the inspirations behind that dream, and our dedication to the dream.

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