Scandinavian Journal of Gastroenterology. 2015; 50: 636–648
REVIEW ARTICLE
Scandinavian epidemiological research in gastroenterology and hepatology
Scand J Gastroenterol Downloaded from informahealthcare.com by Fudan University on 05/15/15 For personal use only.
EINAR S. BJÖRNSSON1,2 & ANDERS EKBOM3 1
Faculty of Medicine, University of Iceland, 2Department of Internal Medicine, Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, Reykjavík, Iceland, and 3Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet and Karolinska University Hospital, Sweden
Abstract In the last decades, a large number of epidemiological studies in gastroenterology and hepatology have originated from the Scandinavian countries. With the help of large health databases, with good validity and other registries related to patient outcomes, researchers from the Scandinavian countries have been able to make some very important contributions to the field. These countries, Sweden, Norway, Finland, Denmark and Iceland, have all universal access to health care and have shown to be ideal for epidemiological research. Population-based studies have been frequent and follow-up studies have been able to describe the temporal trends and changes in phenotypes. Our ability in Scandinavia to follow up defined groups of patients over time has been crucial to learn the natural history of many gastrointestinal and liver diseases and often in a population-based setting. Patient-related outcomes measures will probably gain increasing importance in the future, but Scandinavian gastroenterologists and surgeons are likely to have a better infrastructure for such endeavors compared to most other populations. Thus, there is a bright future for international competitive research within the field of gastrointestinal and liver diseases in Scandinavia.
Key Words: autoimmune hepatitis, drug-induced liver injury, epidemiology, inflammatory bowel disease, primary biliary cirrhosis, primary sclerosing cholangitis
Introduction Good epidemiological research in medicine requires, organized and good access to health care, reliable registries of different health outcomes, and that the patients can easily be traced after contact with the health care. All the Nordic countries fulfill these requirements and therefore these countries have been ideal for epidemiological studies. During the last decades, researchers from the Scandinavian countries have made some important contributions in the field of gastroenterology. Inflammatory bowel disease Scandinavian researchers and Scandinavian Journal of Gastroenterology have been major players in keeping
track on the emerging ‘epidemic’ in inflammatory bowel disease (IBD) during the last 60 years. With the help of Health databases or networks, they were the first, which on a national basis and in a populationbased setting, could describe the temporal trends and changes in phenotypes. That was done in Norway already in the late 1960s by Myren et al. [1], who could demonstrate a trend from very low incidence in the 1950s to 3/100,000 for ulcerative colitis and around 1/100,000 for Crohn’s disease in the late 1960s. Although it is very easy to criticize the approach today, the authors corresponded with all hospitals in Norway, it represent one of the first major efforts to assess the magnitude of IBD as a clinical problem from an international perspective. The authors could also show that there did not seem to be any regional differences, which was something entirely new.
Correspondence: Einar S. Björnsson, Department of Internal Medicine, Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, Reykjavík, Iceland. E-mail: [email protected]
(Received 23 March 2015; accepted 23 March 2015) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2015.1034168
Scand J Gastroenterol Downloaded from informahealthcare.com by Fudan University on 05/15/15 For personal use only.
Scandinavian epidemiological research Similar studies were also done in Sweden and Denmark. In Sweden Norlen et al. [2] and later Bergman and Krause [3] assessed the incidence and prevalence of Crohn’s disease in the middle of Sweden, (the counties of Västmanland and Uppsala) and could demonstrate a substantial increase in incidence over time up to 6/100,000 persons in the early 1970s. Similar figures were presented by Brahme et al. [4] from the southern part of Sweden during the same time period as well as in Stockholm County by Hellers [5]. The figures from the southern part of Sweden are of special interest as a similar survey was done in Copenhagen simultaneously by Binder et al. [6]. The two populations ended up with similar incidence rates, but there was a time lag of about 15 years between the two countries, where Sweden seemingly was affected first. The Danish study also showed the great advantages – Scandinavian clinical researchers have compared with the rest of the world by allowing access to clinical data, in order to better characterize the phenotypes and also allowing long-term follow-up not only from a clinical perspective but also with regard to social prognosis [7]. In the case of ulcerative colitis in Sweden data was scarcer, although the thesis by Samuelsson provided excellent data from 1945 and onward for Uppsala County [8], finally presented in a peer reviewed journal in 2010 [9]. He could demonstrate an increasing trend in incidence from 1945 to 1965. The results were very similar to that already shown in Norway but a substantially higher incidence figure, 6/100,000. Another interesting features were that in a subsequent study by Ekbom et al. [10] for the period 1965–1983, the incidence continued to increase to a peak around 1980 of 14/100,000, and that the figures and trends in middle Sweden for both ulcerative colitis and Crohn’s disease were in total agreement of the figures presented from Rochester, Minnesota, by Sedlack et al. for the same time period [11]. The numbers and trends in Sweden were subsequently confirmed from other parts of Sweden by Nordenvall et al. [12], Stewenius et al. [13], and Tysk and Järnerot [14], Lindberg and Järnerot [15], and Nyhlin and Danielsson [16]. In the case of Finland, it is obvious that the start of the ‘epidemic’ was later than the rest of the Scandinavian countries, in the mid-1980s [17], but subsequently reached an incidence as high as in Norway and in Sweden, 19.6/100,000 for ulcerative colitis and 9.4/100,000 for Crohn’s disease [18]. Another interesting feature is that in a Finnish setting, IBD patients have fewer symptoms and better quality of life compared to other populations although health care utilization was more frequent compared to the normal
637
population [19]. Finnish researchers were also among the first to compare biomarkers and phenotypes between familial and sporadic cases of IBD, without any positive association [20]. Subsequent studies from Norway [21,22,23] and Denmark [24,25] give further credence to the hypothesis that there is an ‘epidemic’ in IBD affecting the northern part in Europe after the second World War, there ulcerative colitis emerges prior to Crohn’s disease. Iceland and Faroe Islands are ideal for incidence studies as case ascertainment can be regarded as complete. It is therefore of special interest that both populations seem to have had similar patterns, and it is obvious that the ‘epidemic’ emerged during the same time span as the rest of Scandinavia [26,27]. Figures from Iceland during the period 1990– 1994 demonstrated an incidence of 16.5/100,000 for ulcerative colitis and 5.5/100,000 for Crohn’s disease [28] and at The Faroe Islands the incidence during the early 1980s was similar to that of Copenhagen [29,30]. Within a European collaborative study in the early 1990s, with participation from both Denmark and Norway, it was obvious that the casefinding was easier and probably more complete than rest of Europe [31]. In the Norwegian setting, this was the start of the IBSEN study, which included both ulcerative colitis and Crohn’s disease patients, identified prospectively 1990–1993 in Southeastern Norway [32,33]. The authors reported the highest incidence so far for ulcerative colitis 21.5/100,000 and just under 6/ 100,000 for Crohn’s disease. These high figures have later been confirmed in other populations in Scandinavia [9,18]. Our ability in Scandinavia to follow up defined groups of patients over time has been crucial to learn about the natural history of IBD over time and followchanges and differences in phenotypes in a population-based setting. This was done already in the 1970s in Uppsala, Sweden [34] and in Copenhagen [35–37]. However, the most important cohort studies from an international perspective have beenthose defined by the IBSEN study and from Copenhagen. These two centers have provided figures after 1, 5 and 10 years after diagnosis with an almost complete follow-up [38–44]. With regard to differences in phenotypes over time, almost all Scandinavian studies demonstrate an increasing proportion of colonic disease and a female dominance for Crohn’s disease, and an increasing proportion of distal colitis and a male predominance for ulcerative colitis. The quality of the Scandinavian researchers has also made it possible to explore the existence of a seasonality pattern in onset or flare ups in IBD. Studies both from Norway [45] and
Scand J Gastroenterol Downloaded from informahealthcare.com by Fudan University on 05/15/15 For personal use only.
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Sweden [46] have shown that the months of fall are overrepresented. Another area of interest, where Scandinavian data have been crucial, is IBD in the pediatric population. In a study from Stockholm, Hildebrand et al. could demonstrate a substantial (threefold) increase in Crohn’s disease during the 1990s [47], a finding that has been confirmed in other populations since then, but not in all. The incidence figures in children have historically been monitored closely in many Scandinavian settings [48–52]. This tradition will be of even greater importance in the future, as there are reasons to believe that this is a new clinical entity, with a very young age at onset and the disease is confined to colon in most patients. The long-term prognosis remains unknown. Thus, there are reasons to believe that Scandinavian data will be of utmost importance in the future to characterize the long-term disease process. The access to patients for etiological research gave Scandinavian an edge in case–control studies with regard to environmental factors especially diet [53,54], smoking [8,55], snuff use [56], early weaning [57] and antibiotic use [58]. The findings in the collaborative study emanating from Israel [59] of appendectomy as a protective factor for ulcerative colitis could be explored further by the use of Swedish [60] and Danish [61] Health Care databases, where the authors could show that it is appendicitis not appendectomy, which confers the protection. Scandinavian data were also the first to make it possible to quantify the strength of the familial association in IBD and between ulcerative colitis and Crohn’s disease [62,63]. The linkage to the Swedish Twin Registry provided further insight of stronger genetic component in Crohn’s disease compared to ulcerative colitis [64]. These findings were later confirmed in a Swedish–Danish collaborative study [65]. Health economics in IBD has also been pioneered by the use of Scandinavian Health Databases, not only with regard to heath care utilization [66], but also more importantly to assess the indirect cost as opposed to direct costs. In one of the first studies of this outcome, Blomquist and Ekbom [67] could show that the majority of the costs for IBD patients for the society was due to the indirect costs, thus paving the way for the introduction of expensive remedies such as the new biologics introduced in the late 1990s. Lately, has also the notion that surgery would lead to savings with regard to the indirect costs been challenged. In a Swedish study, Neovius et al. [68] could show that ulcerative colitis patient did not return to the work force to the extent, they were prior to a colectomy. In the future, there is a need for better interactions between patients and the health-care system, as many
IBD patients seek alternative remedies [69]. Patientrelated outcomes measures will gain increasing importance, but Scandinavian gastroenterologist and surgeons will probably have a better infrastructure for such endeavors compared to most other populations. Thus, there is a bright future for international competitive research within the field of IBD in Scandinavia. Hepatology Chronic hepatitis and autoimmune hepatitis Prior to the identification of hepatitis C, chronic active hepatitis was the term used that in retrospect included both patients with viral hepatitis, called nonA-non-B hepatitis and autoimmune hepatitis (AIH). One of the first studies undertaken by the Swedish Internal Medicine Liver Club (SILC), led by Professor Rolf Olsson from Gothenburg Sweden was on chronic active hepatitis [70]. This research activity among Swedish gastroenterologists and hepatologists from academic centers proved to be very productive, leading to >60 publications in international peerreviewed journals. In this first SILC study, an epidemiologic study covering approximately one-third of the adult Swedish population, showed an annual incidence of chronic active hepatitis of 1.6 cases per 100,000 inhabitants per year. The results of the study should be put in the context of the detection of hepatitis C and improved serological testing for hepatitis B. Interestingly, the prevalence of ulcerative colitis and gluten enteropathy was remarkably high in idiopathic chronic active hepatitis. A study from Malmö Sweden found frequent occurrence of nonspecific gliadin antibodies in different chronic liver diseases [71]. Celiac disease was found to be more prevalent than expected among patients with autoimmune chronic active hepatitis but not among those with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) [71]. In contrast to patients with AIH in southern Europe, who not infrequently have liver/kidney microsomal autoantibodies type 1 (LKM-1), no LKM-1 reactivity was observed in a cohort of Swedish AIH patients [72]. Antineutrophil cytoplasmic antibodies were found to be frequent in patients with various chronic liver diseases and although occurring more frequently in autoimmune liver disease they were found to have low specificity and sensitivity for autoimmune liver disease [73]. In a study published in the current journal on the epidemiology of chronic liver disease, initiated by Professor Helge Bell in Oslo, during a 10-year period 25 patients with AIH were diagnosed [74]. The mean annual incidence of AIH per 100,000 was
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Scandinavian epidemiological research 1.9 and the point prevalence was 16.9 [74]. A multicenter study from Sweden with a much larger cohort of patients aimed to investigate the incidence, prevalence, diagnostic tradition and initial clinical presentation of AIH [75]. The incidence was found to be lower than in the study from Norway, 0.85/100,000 and the point prevalence 10.7/100,00 and 76% were females [75]. The agerelated incidence curve was found to be bimodal, men were found to have an incidence peak in the late teens, whereas women had a peak after menopause. Onethird of patients had cirrhosis at diagnosis and autoantibodies of AIH type 1 were found in almost 80% of cases and other concomitant autoimmune disorders in almost 50% of patients [75]. Further follow-up of the same cohort of 473 patients, revealed that apart from the 30% with cirrhosis at diagnosis, another 10% developed cirrhosis during follow-up [76]. Markedly elevated alanine aminotransferase levels at presentation, with intact synthetic capacity were correlated with a better outcome. High international normalized ratio at diagnosis was the only risk factor predicting a need for later liver transplantation. Overall life expectancy was generally favorable but most deaths were liver-related. Histological cirrhosis, hepatic decompensation and nonresponse to initial immunosuppressive therapy were all factors related to a worse outcome. In a study of 634 Swedish AIH patients, a slightly enhanced risk for malignancies was observed [77]. The risk of hepatobiliary cancer was increased but hepatocellular cancer (HCC) was only found in cirrhotic patients, and in only 10/248 (4%) of cirrhotics [77]. The annual risk of HCC was 0.3% and under the cut-off 1.5% postulated for the HCC surveillance. In a recent study from Denmark on the epidemiology of AIH, all Danish citizens from 1994 to 2012 were identified from nationwide health-care registries (n = 1721 patients) [78]. The incidence was found to be 1.68 per 100,000, slightly lower than the 1.9 incidence rate in the Norwegian study by Boberg and Bell [74]. In line with the Swedish AIH study [77], ~30% had cirrhosis at diagnosis and similar cumulative risk of HCC, 0.7% over 10 years from diagnosis [78]. In the first year after diagnosis, the AIH patients had six-fold higher mortality than the general population. In contrast with other studies men had higher mortality than women despite similar prevalence of cirrhosis at presentation. Although the authors tried to control for confounders such as alcoholism and comorbidity, the limitation of large registry studies like this one is a lack of detailed phenotypic data, clinical management and compliance with treatment. The incidence was found to have increased over the study period, although it is not entirely clear if this was due to better registration of diagnostic codes and/or change in case ascertainment.
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Primary sclerosing cholangitis The PSC is more common in Northern Europe and North America than in the south of Europe or South America. Much of the epidemiological data and the natural history of this disease are derived from studies from the Nordic countries. One of the largest cohorts of PSC patients originates from Sweden [79]. Ulrika Broome from Stockholm leads this pioneer study and many other studies on PSC. Unfortunately, Ulrika died as a young researcher and a clinician and is missed by many, both patients and colleagues. In this early study, the median survival from diagnosis to death or liver transplantation was 12 years. Recent studies show though longer overall survival. In line with other studies, 8% developed cholangiocarcinoma, the most feared complication of PSC. In a classical paper from the SILC, the prevalence of PSC among patients with IBD was 3.7% [80]. The relationship between IBD and PSC has also been explored from the PSC point of view in a study from Norway [81]. A total of 84% of the PSC patients (n = 155) had IBD, in this prospective study [81]. Interestingly 65% of patients had no or sparse IBD symptoms and inflammatory findings were more frequently encountered histologically than endoscopically. Rectal sparing was frequent (65%) and of interest was that those who had undergone liver transplantation had both lower histological and clinical IBD activity. In a Swedish study, the risk of PSC and IBD among first-degree relatives of PSC patients was investigated [82]. The risk of PSC was found to be increased in offsprings, siblings and parents of the PSC patient cohort. The hazard ratio for ulcerative colitis was increased in the first-degree relatives. Interestingly, the risk of UC was also increased in relatives PSC patients without UC, indicating that PSC and UC share genetic susceptibility. Hepatic and extrahepatic malignancies have shown to be increased in PSC particularly during the first year after diagnosis [83,84]. In a study from Norway, coffee consumption and smoking were found to protect against the development of PSC [85]. Most data on the type of PSC called small duct PSC comes from researchers from the Nordic countries [86–88]. This type of PSC, with clinical, biochemical and histological features similar to large duct PSC has been shown to have a better prognosis and not to be associated with the development of cholangiocarcinoma, whereas this malignancy develops in 10–20% of PSC patients depending on the duration of follow-up. Population-based studies on the epidemiology of PSC are sparse. In a study from the west part of Sweden (Vastra Götaland), with a population of
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~1.5 million, a total of 199 patients with PSC were identified during the period of 1992–2005 [89]. The annual incidence was 1.22 per 100,000 in the total adult population. The overall incidence rate increased significantly over the study period. The point prevalence at the end of 2005, was 16.2/100,000, for men 23.7/100,000 and for women 8.9/100,000, which is the highest reported to date. This is also the first study to report a significantly increasing trend in the incidence of PSC. This implies that the medical burden of PSC may be higher than estimated previously. This is clinically important as this will increase the need for liver transplantation and lead to increased morbidity and mortality from PSC.
Primary biliary cirrhosis Studies on the incidence and prevalence of PBC started to appear in the early 1980s [90–92]. PBC was previously considered to be more prevalent in Europe and North America than elsewhere [93,94] but this now being questioned as high prevalence has been shown recently in China [95]. Apart from the above-mentioned studies from Sweden, PBC epidemiology has also been studied in Norway [74] and more recently in Finland [96]. The study from Finland demonstrated increasing incidence and prevalence. Most studies showing an increased incidence with time are from 1980s and 1990s. A recent study from Iceland demonstrated the highest incidence of PBC previously reported, 2.5 patients per 100,000 inhabitants and year [97] together with 2.7 per 100,000 in Minnesota [98] and 3 per 100,000 in Canada [99]. Also the prevalence of PBC at the end of the study of 38 cases per 100,000 [97] is among the highest together with the study from Minnesota and Newcastle England [100]. The reason for higher incidence and prevalence in Iceland than in the other Nordic countries [74,90– 92,96] is probably related to the methodology used for casefinding strategies. In line with casefinding strategies in Minnesota [98] and Newcastle [100], a search was undertaken in the centralized database of antimitochondrial measurements (AMA) and computerized diagnoses and pathological registries [97]. Thus, as 95% of PBC patients have positive AMA and pathology registries were also utilized to find cases, it is unlikely that many cases were missed. The prognosis among the Icelandic patients was relatively favorable compared with other population-based cohorts. The median survival after diagnosis was 15 years, almost 6 years longer than that reported from Newcastle [101], where 10-year survival was just under 50% compared with 68% survival in the
Icelandic study and also better than the 59% 10-years survival in Minnesota [98]. It is of interest that almost 20% of the Icelandic PBC patients died of different types of malignancies (other than HCC). An overall excess risk for cancer has also been observed in a Swedish population-based study on PBC patients [102].
Alcoholic liver disease and other types of cirrhosis The natural history of gastrointestinal bleeding in cirrhosis was studied early in Denmark using prospectively collected data of 532 patients included in a randomized clinical trial with a regular follow-up of up to 12 years [103]. These cirrhotic patients were found to have very unfavorable prognosis. In these patients, the fatality from variceal bleeding was 82%. The risk of rebleeding from varices was 81%, and 4 years after the first bleeding the cumulative survival had decreased to
REVIEW ARTICLE
Scandinavian epidemiological research in gastroenterology and hepatology
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EINAR S. BJÖRNSSON1,2 & ANDERS EKBOM3 1
Faculty of Medicine, University of Iceland, 2Department of Internal Medicine, Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, Reykjavík, Iceland, and 3Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet and Karolinska University Hospital, Sweden
Abstract In the last decades, a large number of epidemiological studies in gastroenterology and hepatology have originated from the Scandinavian countries. With the help of large health databases, with good validity and other registries related to patient outcomes, researchers from the Scandinavian countries have been able to make some very important contributions to the field. These countries, Sweden, Norway, Finland, Denmark and Iceland, have all universal access to health care and have shown to be ideal for epidemiological research. Population-based studies have been frequent and follow-up studies have been able to describe the temporal trends and changes in phenotypes. Our ability in Scandinavia to follow up defined groups of patients over time has been crucial to learn the natural history of many gastrointestinal and liver diseases and often in a population-based setting. Patient-related outcomes measures will probably gain increasing importance in the future, but Scandinavian gastroenterologists and surgeons are likely to have a better infrastructure for such endeavors compared to most other populations. Thus, there is a bright future for international competitive research within the field of gastrointestinal and liver diseases in Scandinavia.
Key Words: autoimmune hepatitis, drug-induced liver injury, epidemiology, inflammatory bowel disease, primary biliary cirrhosis, primary sclerosing cholangitis
Introduction Good epidemiological research in medicine requires, organized and good access to health care, reliable registries of different health outcomes, and that the patients can easily be traced after contact with the health care. All the Nordic countries fulfill these requirements and therefore these countries have been ideal for epidemiological studies. During the last decades, researchers from the Scandinavian countries have made some important contributions in the field of gastroenterology. Inflammatory bowel disease Scandinavian researchers and Scandinavian Journal of Gastroenterology have been major players in keeping
track on the emerging ‘epidemic’ in inflammatory bowel disease (IBD) during the last 60 years. With the help of Health databases or networks, they were the first, which on a national basis and in a populationbased setting, could describe the temporal trends and changes in phenotypes. That was done in Norway already in the late 1960s by Myren et al. [1], who could demonstrate a trend from very low incidence in the 1950s to 3/100,000 for ulcerative colitis and around 1/100,000 for Crohn’s disease in the late 1960s. Although it is very easy to criticize the approach today, the authors corresponded with all hospitals in Norway, it represent one of the first major efforts to assess the magnitude of IBD as a clinical problem from an international perspective. The authors could also show that there did not seem to be any regional differences, which was something entirely new.
Correspondence: Einar S. Björnsson, Department of Internal Medicine, Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, Reykjavík, Iceland. E-mail: [email protected]
(Received 23 March 2015; accepted 23 March 2015) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2015.1034168
Scand J Gastroenterol Downloaded from informahealthcare.com by Fudan University on 05/15/15 For personal use only.
Scandinavian epidemiological research Similar studies were also done in Sweden and Denmark. In Sweden Norlen et al. [2] and later Bergman and Krause [3] assessed the incidence and prevalence of Crohn’s disease in the middle of Sweden, (the counties of Västmanland and Uppsala) and could demonstrate a substantial increase in incidence over time up to 6/100,000 persons in the early 1970s. Similar figures were presented by Brahme et al. [4] from the southern part of Sweden during the same time period as well as in Stockholm County by Hellers [5]. The figures from the southern part of Sweden are of special interest as a similar survey was done in Copenhagen simultaneously by Binder et al. [6]. The two populations ended up with similar incidence rates, but there was a time lag of about 15 years between the two countries, where Sweden seemingly was affected first. The Danish study also showed the great advantages – Scandinavian clinical researchers have compared with the rest of the world by allowing access to clinical data, in order to better characterize the phenotypes and also allowing long-term follow-up not only from a clinical perspective but also with regard to social prognosis [7]. In the case of ulcerative colitis in Sweden data was scarcer, although the thesis by Samuelsson provided excellent data from 1945 and onward for Uppsala County [8], finally presented in a peer reviewed journal in 2010 [9]. He could demonstrate an increasing trend in incidence from 1945 to 1965. The results were very similar to that already shown in Norway but a substantially higher incidence figure, 6/100,000. Another interesting features were that in a subsequent study by Ekbom et al. [10] for the period 1965–1983, the incidence continued to increase to a peak around 1980 of 14/100,000, and that the figures and trends in middle Sweden for both ulcerative colitis and Crohn’s disease were in total agreement of the figures presented from Rochester, Minnesota, by Sedlack et al. for the same time period [11]. The numbers and trends in Sweden were subsequently confirmed from other parts of Sweden by Nordenvall et al. [12], Stewenius et al. [13], and Tysk and Järnerot [14], Lindberg and Järnerot [15], and Nyhlin and Danielsson [16]. In the case of Finland, it is obvious that the start of the ‘epidemic’ was later than the rest of the Scandinavian countries, in the mid-1980s [17], but subsequently reached an incidence as high as in Norway and in Sweden, 19.6/100,000 for ulcerative colitis and 9.4/100,000 for Crohn’s disease [18]. Another interesting feature is that in a Finnish setting, IBD patients have fewer symptoms and better quality of life compared to other populations although health care utilization was more frequent compared to the normal
637
population [19]. Finnish researchers were also among the first to compare biomarkers and phenotypes between familial and sporadic cases of IBD, without any positive association [20]. Subsequent studies from Norway [21,22,23] and Denmark [24,25] give further credence to the hypothesis that there is an ‘epidemic’ in IBD affecting the northern part in Europe after the second World War, there ulcerative colitis emerges prior to Crohn’s disease. Iceland and Faroe Islands are ideal for incidence studies as case ascertainment can be regarded as complete. It is therefore of special interest that both populations seem to have had similar patterns, and it is obvious that the ‘epidemic’ emerged during the same time span as the rest of Scandinavia [26,27]. Figures from Iceland during the period 1990– 1994 demonstrated an incidence of 16.5/100,000 for ulcerative colitis and 5.5/100,000 for Crohn’s disease [28] and at The Faroe Islands the incidence during the early 1980s was similar to that of Copenhagen [29,30]. Within a European collaborative study in the early 1990s, with participation from both Denmark and Norway, it was obvious that the casefinding was easier and probably more complete than rest of Europe [31]. In the Norwegian setting, this was the start of the IBSEN study, which included both ulcerative colitis and Crohn’s disease patients, identified prospectively 1990–1993 in Southeastern Norway [32,33]. The authors reported the highest incidence so far for ulcerative colitis 21.5/100,000 and just under 6/ 100,000 for Crohn’s disease. These high figures have later been confirmed in other populations in Scandinavia [9,18]. Our ability in Scandinavia to follow up defined groups of patients over time has been crucial to learn about the natural history of IBD over time and followchanges and differences in phenotypes in a population-based setting. This was done already in the 1970s in Uppsala, Sweden [34] and in Copenhagen [35–37]. However, the most important cohort studies from an international perspective have beenthose defined by the IBSEN study and from Copenhagen. These two centers have provided figures after 1, 5 and 10 years after diagnosis with an almost complete follow-up [38–44]. With regard to differences in phenotypes over time, almost all Scandinavian studies demonstrate an increasing proportion of colonic disease and a female dominance for Crohn’s disease, and an increasing proportion of distal colitis and a male predominance for ulcerative colitis. The quality of the Scandinavian researchers has also made it possible to explore the existence of a seasonality pattern in onset or flare ups in IBD. Studies both from Norway [45] and
Scand J Gastroenterol Downloaded from informahealthcare.com by Fudan University on 05/15/15 For personal use only.
638
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Sweden [46] have shown that the months of fall are overrepresented. Another area of interest, where Scandinavian data have been crucial, is IBD in the pediatric population. In a study from Stockholm, Hildebrand et al. could demonstrate a substantial (threefold) increase in Crohn’s disease during the 1990s [47], a finding that has been confirmed in other populations since then, but not in all. The incidence figures in children have historically been monitored closely in many Scandinavian settings [48–52]. This tradition will be of even greater importance in the future, as there are reasons to believe that this is a new clinical entity, with a very young age at onset and the disease is confined to colon in most patients. The long-term prognosis remains unknown. Thus, there are reasons to believe that Scandinavian data will be of utmost importance in the future to characterize the long-term disease process. The access to patients for etiological research gave Scandinavian an edge in case–control studies with regard to environmental factors especially diet [53,54], smoking [8,55], snuff use [56], early weaning [57] and antibiotic use [58]. The findings in the collaborative study emanating from Israel [59] of appendectomy as a protective factor for ulcerative colitis could be explored further by the use of Swedish [60] and Danish [61] Health Care databases, where the authors could show that it is appendicitis not appendectomy, which confers the protection. Scandinavian data were also the first to make it possible to quantify the strength of the familial association in IBD and between ulcerative colitis and Crohn’s disease [62,63]. The linkage to the Swedish Twin Registry provided further insight of stronger genetic component in Crohn’s disease compared to ulcerative colitis [64]. These findings were later confirmed in a Swedish–Danish collaborative study [65]. Health economics in IBD has also been pioneered by the use of Scandinavian Health Databases, not only with regard to heath care utilization [66], but also more importantly to assess the indirect cost as opposed to direct costs. In one of the first studies of this outcome, Blomquist and Ekbom [67] could show that the majority of the costs for IBD patients for the society was due to the indirect costs, thus paving the way for the introduction of expensive remedies such as the new biologics introduced in the late 1990s. Lately, has also the notion that surgery would lead to savings with regard to the indirect costs been challenged. In a Swedish study, Neovius et al. [68] could show that ulcerative colitis patient did not return to the work force to the extent, they were prior to a colectomy. In the future, there is a need for better interactions between patients and the health-care system, as many
IBD patients seek alternative remedies [69]. Patientrelated outcomes measures will gain increasing importance, but Scandinavian gastroenterologist and surgeons will probably have a better infrastructure for such endeavors compared to most other populations. Thus, there is a bright future for international competitive research within the field of IBD in Scandinavia. Hepatology Chronic hepatitis and autoimmune hepatitis Prior to the identification of hepatitis C, chronic active hepatitis was the term used that in retrospect included both patients with viral hepatitis, called nonA-non-B hepatitis and autoimmune hepatitis (AIH). One of the first studies undertaken by the Swedish Internal Medicine Liver Club (SILC), led by Professor Rolf Olsson from Gothenburg Sweden was on chronic active hepatitis [70]. This research activity among Swedish gastroenterologists and hepatologists from academic centers proved to be very productive, leading to >60 publications in international peerreviewed journals. In this first SILC study, an epidemiologic study covering approximately one-third of the adult Swedish population, showed an annual incidence of chronic active hepatitis of 1.6 cases per 100,000 inhabitants per year. The results of the study should be put in the context of the detection of hepatitis C and improved serological testing for hepatitis B. Interestingly, the prevalence of ulcerative colitis and gluten enteropathy was remarkably high in idiopathic chronic active hepatitis. A study from Malmö Sweden found frequent occurrence of nonspecific gliadin antibodies in different chronic liver diseases [71]. Celiac disease was found to be more prevalent than expected among patients with autoimmune chronic active hepatitis but not among those with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) [71]. In contrast to patients with AIH in southern Europe, who not infrequently have liver/kidney microsomal autoantibodies type 1 (LKM-1), no LKM-1 reactivity was observed in a cohort of Swedish AIH patients [72]. Antineutrophil cytoplasmic antibodies were found to be frequent in patients with various chronic liver diseases and although occurring more frequently in autoimmune liver disease they were found to have low specificity and sensitivity for autoimmune liver disease [73]. In a study published in the current journal on the epidemiology of chronic liver disease, initiated by Professor Helge Bell in Oslo, during a 10-year period 25 patients with AIH were diagnosed [74]. The mean annual incidence of AIH per 100,000 was
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Scandinavian epidemiological research 1.9 and the point prevalence was 16.9 [74]. A multicenter study from Sweden with a much larger cohort of patients aimed to investigate the incidence, prevalence, diagnostic tradition and initial clinical presentation of AIH [75]. The incidence was found to be lower than in the study from Norway, 0.85/100,000 and the point prevalence 10.7/100,00 and 76% were females [75]. The agerelated incidence curve was found to be bimodal, men were found to have an incidence peak in the late teens, whereas women had a peak after menopause. Onethird of patients had cirrhosis at diagnosis and autoantibodies of AIH type 1 were found in almost 80% of cases and other concomitant autoimmune disorders in almost 50% of patients [75]. Further follow-up of the same cohort of 473 patients, revealed that apart from the 30% with cirrhosis at diagnosis, another 10% developed cirrhosis during follow-up [76]. Markedly elevated alanine aminotransferase levels at presentation, with intact synthetic capacity were correlated with a better outcome. High international normalized ratio at diagnosis was the only risk factor predicting a need for later liver transplantation. Overall life expectancy was generally favorable but most deaths were liver-related. Histological cirrhosis, hepatic decompensation and nonresponse to initial immunosuppressive therapy were all factors related to a worse outcome. In a study of 634 Swedish AIH patients, a slightly enhanced risk for malignancies was observed [77]. The risk of hepatobiliary cancer was increased but hepatocellular cancer (HCC) was only found in cirrhotic patients, and in only 10/248 (4%) of cirrhotics [77]. The annual risk of HCC was 0.3% and under the cut-off 1.5% postulated for the HCC surveillance. In a recent study from Denmark on the epidemiology of AIH, all Danish citizens from 1994 to 2012 were identified from nationwide health-care registries (n = 1721 patients) [78]. The incidence was found to be 1.68 per 100,000, slightly lower than the 1.9 incidence rate in the Norwegian study by Boberg and Bell [74]. In line with the Swedish AIH study [77], ~30% had cirrhosis at diagnosis and similar cumulative risk of HCC, 0.7% over 10 years from diagnosis [78]. In the first year after diagnosis, the AIH patients had six-fold higher mortality than the general population. In contrast with other studies men had higher mortality than women despite similar prevalence of cirrhosis at presentation. Although the authors tried to control for confounders such as alcoholism and comorbidity, the limitation of large registry studies like this one is a lack of detailed phenotypic data, clinical management and compliance with treatment. The incidence was found to have increased over the study period, although it is not entirely clear if this was due to better registration of diagnostic codes and/or change in case ascertainment.
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Primary sclerosing cholangitis The PSC is more common in Northern Europe and North America than in the south of Europe or South America. Much of the epidemiological data and the natural history of this disease are derived from studies from the Nordic countries. One of the largest cohorts of PSC patients originates from Sweden [79]. Ulrika Broome from Stockholm leads this pioneer study and many other studies on PSC. Unfortunately, Ulrika died as a young researcher and a clinician and is missed by many, both patients and colleagues. In this early study, the median survival from diagnosis to death or liver transplantation was 12 years. Recent studies show though longer overall survival. In line with other studies, 8% developed cholangiocarcinoma, the most feared complication of PSC. In a classical paper from the SILC, the prevalence of PSC among patients with IBD was 3.7% [80]. The relationship between IBD and PSC has also been explored from the PSC point of view in a study from Norway [81]. A total of 84% of the PSC patients (n = 155) had IBD, in this prospective study [81]. Interestingly 65% of patients had no or sparse IBD symptoms and inflammatory findings were more frequently encountered histologically than endoscopically. Rectal sparing was frequent (65%) and of interest was that those who had undergone liver transplantation had both lower histological and clinical IBD activity. In a Swedish study, the risk of PSC and IBD among first-degree relatives of PSC patients was investigated [82]. The risk of PSC was found to be increased in offsprings, siblings and parents of the PSC patient cohort. The hazard ratio for ulcerative colitis was increased in the first-degree relatives. Interestingly, the risk of UC was also increased in relatives PSC patients without UC, indicating that PSC and UC share genetic susceptibility. Hepatic and extrahepatic malignancies have shown to be increased in PSC particularly during the first year after diagnosis [83,84]. In a study from Norway, coffee consumption and smoking were found to protect against the development of PSC [85]. Most data on the type of PSC called small duct PSC comes from researchers from the Nordic countries [86–88]. This type of PSC, with clinical, biochemical and histological features similar to large duct PSC has been shown to have a better prognosis and not to be associated with the development of cholangiocarcinoma, whereas this malignancy develops in 10–20% of PSC patients depending on the duration of follow-up. Population-based studies on the epidemiology of PSC are sparse. In a study from the west part of Sweden (Vastra Götaland), with a population of
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~1.5 million, a total of 199 patients with PSC were identified during the period of 1992–2005 [89]. The annual incidence was 1.22 per 100,000 in the total adult population. The overall incidence rate increased significantly over the study period. The point prevalence at the end of 2005, was 16.2/100,000, for men 23.7/100,000 and for women 8.9/100,000, which is the highest reported to date. This is also the first study to report a significantly increasing trend in the incidence of PSC. This implies that the medical burden of PSC may be higher than estimated previously. This is clinically important as this will increase the need for liver transplantation and lead to increased morbidity and mortality from PSC.
Primary biliary cirrhosis Studies on the incidence and prevalence of PBC started to appear in the early 1980s [90–92]. PBC was previously considered to be more prevalent in Europe and North America than elsewhere [93,94] but this now being questioned as high prevalence has been shown recently in China [95]. Apart from the above-mentioned studies from Sweden, PBC epidemiology has also been studied in Norway [74] and more recently in Finland [96]. The study from Finland demonstrated increasing incidence and prevalence. Most studies showing an increased incidence with time are from 1980s and 1990s. A recent study from Iceland demonstrated the highest incidence of PBC previously reported, 2.5 patients per 100,000 inhabitants and year [97] together with 2.7 per 100,000 in Minnesota [98] and 3 per 100,000 in Canada [99]. Also the prevalence of PBC at the end of the study of 38 cases per 100,000 [97] is among the highest together with the study from Minnesota and Newcastle England [100]. The reason for higher incidence and prevalence in Iceland than in the other Nordic countries [74,90– 92,96] is probably related to the methodology used for casefinding strategies. In line with casefinding strategies in Minnesota [98] and Newcastle [100], a search was undertaken in the centralized database of antimitochondrial measurements (AMA) and computerized diagnoses and pathological registries [97]. Thus, as 95% of PBC patients have positive AMA and pathology registries were also utilized to find cases, it is unlikely that many cases were missed. The prognosis among the Icelandic patients was relatively favorable compared with other population-based cohorts. The median survival after diagnosis was 15 years, almost 6 years longer than that reported from Newcastle [101], where 10-year survival was just under 50% compared with 68% survival in the
Icelandic study and also better than the 59% 10-years survival in Minnesota [98]. It is of interest that almost 20% of the Icelandic PBC patients died of different types of malignancies (other than HCC). An overall excess risk for cancer has also been observed in a Swedish population-based study on PBC patients [102].
Alcoholic liver disease and other types of cirrhosis The natural history of gastrointestinal bleeding in cirrhosis was studied early in Denmark using prospectively collected data of 532 patients included in a randomized clinical trial with a regular follow-up of up to 12 years [103]. These cirrhotic patients were found to have very unfavorable prognosis. In these patients, the fatality from variceal bleeding was 82%. The risk of rebleeding from varices was 81%, and 4 years after the first bleeding the cumulative survival had decreased to
