Increased prevalence of primary sclerosing cholangitis among first-degree relatives

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1 Journal of Hepatology 42 (2005) Increased prevalence of primary sclerosing cholangitis among first-degree Annika Bergquist*, Greger Lindberg, Susanne Saarinen, Ulrika Broomé Department of Gastroenterology and Hepatology, Karolinska University Hospital, Huddinge, Karolinska Institutet, Stockholm, Huddinge, Sweden Background/Aims: The aim of the present study was to investigate the familial occurrence of autoimmune diseases in a large group of patients with primary sclerosing cholangitis (PSC). Methods: All patients treated at Huddinge University Hospital between 1984 and 1999 were included (nz145). For every patient and inflammatory bowel disease (IBD) (nz126) we randomly selected a control patient with IBD (nz126), matched for age, sex and type of IBD. A questionnaire comprising information about autoimmune diseases among first-degree was answered by all patients and controls. Results: We identified 22 index cases from 21 families with a first-degree relative with either chronic liver disease and/or IBD. Five patients had a first-degree relative (3.4%). The prevalence of PSC among first-degree was 0.7% (5/717). In siblings the prevalence was 1.5% (4/269). The prevalence of first-degree with autoimmune diseases outside the liver was similar in PSC patients and controls. Conclusions: First-degree of patients have a PSC prevalence of 0.7%. This represents a nearly 100-fold increased risk of developing PSC compared with the general population, supporting the hypothesis that genetic factors are of importance for development of PSC. q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. 1. Introduction The aetiology of PSC is unknown but the disease is generally defined as an autoimmune liver disease. This is supported by the presence of autoantibodies and increased levels of specific T-cells found in the portal tracts in the liver [1,2]. In addition, the close association between IBD and PSC, with approximately 80% of PSC patients having a concomitant IBD [3,4], and the fact that patients have an increased frequency of other autoimmune disorders also speaks in favour of involvement of the immune system in the aetiopathogenesis of PSC [5]. However, PSC lacks some characteristics of autoimmune diseases such as a Received 2 June 2004; received in revised form 20 September 2004; accepted 19 October 2004; available online 2 November 2004 * Corresponding author. Tel.: C ; fax: C address: annika.bergquist@medhs.ki.se (A. Bergquist). Abbreviations IBD, inflammatory bowel disease; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; UC, ulcerative colitis; CD, Crohn s disease; ERCP, endoscopic retrograde cholangio pancreatico graphy; MRCP, magnetic resonance cholangio pancreatico graphy. female preponderance and good response to immunosuppression. The genetic basis of human autoimmune diseases is receiving increased attention. It is well established that genetic factors play an important role in modulating autoimmune diseases by conferring susceptibility to or providing protection from disease onset, progression and/or severity. The importance of genetic factors for the development of PSC is not fully understood. Studies have shown an association between PSC and HLA alleles such as B8, DR B1*03, and DRB1*13 [6] and this speaks in favour of genetic factors being important for the susceptibility of PSC. Further evidence supporting a genetic predisposition for PSC comes from a few case reports of familial occurrence of PSC [7 9]. However, no evaluation of familial occurrence in a large group of patients has previously been done. The aim of the present study was to investigate the familial occurrence of autoimmune diseases, including chronic liver diseases, IBD, rheumatoid arthritis, diabetes, thyroid disease and other autoimmune diseases in a large group of patients. Since PSC is strongly associated with IBD we also studied a control group of patients with IBD /$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /j.jhep

2 A. Bergquist et al. / Journal of Hepatology 42 (2005) but without PSC for comparison. This was done in order to evaluate if autoimmune diseases among first-degree were associated to PSC itself, or to IBD, since it is well known that first-degree to patients with IBD have an increased risk for development of IBD. 2. Methods All living patients with a well-defined PSC who had been treated at Huddinge University Hospital between 1984 and 1999 were included in the study (nz145). To every patient and IBD (nz126) we selected a control with IBD without PSC (nz126) who had been treated at our hospital during the same period of time as the cases. The control IBD patients were selected from a computerised register of all IBD patients at Huddinge University Hospital. Controls with normal liver function tests matched for sex, age and type of IBD were selected. All the controls had normal liver function tests at least at three occasions with 6 months apart. A questionnaire comprising information about presence of liver disease, IBD, diabetes, rheumatoid arthritis, thyroid disease or other autoimmune disease in first-degree was sent by mail to all patients and controls. All patients who did not reply by mail were reminded by telephone. After that the patients either sent in the questionnaire or answered the questions over the phone. All patients accepted to be included into the study and information was elicited from all patients. The diagnosis of PSC was based on biochemical, histological and cholangiographic features [10]. Small bile duct PSC was defined as patients with cholestatic liver function tests and characteristic histological features of PSC but a normal cholangiograms [11]. Information about PSC and IBD was retrieved from patients medical records. Onset of PSC was defined as time for first ERCP/MRCP consistent. In patients with small bile duct PSC the time for first normal ERCP/MRCP was defined as onset of disease. The confluence of the bile ducts at the hilum was used for distinguishing between extrahepatic and intrahepatic portions of the biliary system. Symptoms of PSC (jaundice, right upper quadrant pain, pruritus, ascites and variceal haemorrhage) were registered. The diagnosis of UC was based on a typical history and characteristic endoscopic and histological findings [12]. All 145 patients had undergone colonoscopy to look for IBD and no endoscopical or histological signs of IBD were found in the non-ibd PSC patients. The diagnosis of PSC and IBD in the of PSC patients was verified with MRCP in three cases and ERCP in two. We were not able to verify the diagnosis of other autoimmune diseases among the in the PSC group or controls. The Ethics Committee of Karolinska Institutet approved the study Statistics Nominal data were analysed using the Chi-square test or Fischer s exact test whenever appropriate. Continuous variables were assumed to have nonnormal distributions. Hence we used the Mann Whitney U-test for comparisons of continuous variables. 3. Results 3.1. Autoimmune diseases in first-degree to patients with primary sclerosing cholangitis Clinical characteristics of our patients are given in Table 1. We identified 22 index cases from 21 families with a first-degree relative (mother, father, brother, sister or child) that either had chronic liver disease or IBD (Table 2). Eleven of 145 PSC (8%) patients had a first-degree relative with liver disease. Five patients with PSC had a first-degree relative (3.4%). No index Table 1 Clinical characteristics of 145 PSC patients Clinical characteristics PSC patients (nz145) Age at onset of PSC (meangsd) 36 (G15) years Sex distribution men/women 69% (100/145) / 31% (45/145) Symptoms (data missing in three cases) 77% (109/142) Liver transplantation 41% (60/145) Cholangiographic distribution of PSC (Data missing in 10 patients) Extra-and intrahepatic involvement 70% (94/135) Intrahepatic changes 22% (30/135) Extrahepatic changes 2% (3/135) Small bile duct PSC 6% (8/135) Development of hepatobiliary carcinoma 9% (13/145) Inflammatory bowel disease 87% (126/145) (UC/CD) 85% UC/15% CD Colectomy 29% (36/145) UC, ulcerative colitis; CD, Crohn s disease. patient had a child. The diagnosis of PSC was verified and fulfilled the diagnostic criteria for PSC in all five. All of them had both extra and intrahepatic distribution of their PSC. Sixteen of 145 PSC patients had a first-degree relative with IBD (Table 2). The number of siblings (nz269), parents (nz290) and children (nz158) in the PSC group was altogether 717. The information about number of children was not available in 10 PSC patients. The prevalence of PSC in first-degree to PSC patients was 0.7% (5/717). In siblings to PSC patients the prevalence of PSC was 1.5% (4/269). Patients without IBD had a higher prevalence of IBD among firstdegree, compared to PSC patients with IBD, 26% (5/19) versus 9% (11/126) (P!0.05). The number of siblings was similar in PSC-IBD patients and controls, 235 and 245, respectively. In three patients unspecified chronic liver disease was reported in a first-degree relative. The first case was a mother of a 77-year old PSC patient. His mother was born in 1898 and died at 92 years of age of what was a suspected a liver cancer. The second was a father of Table 2 Liver disease and inflammatory bowel disease in first-degree to 22 PSC patients with and without IBD Patients and colitis Patients and colitis with colitis a 4 b a One mother had ulcerative colitis and autoimmune hepatitis. b Alcoholic liver disease in two. with other liver disease

3 254 A. Bergquist et al. / Journal of Hepatology 42 (2005) a 65-year old PSC patient who died at 77 years of age due to liver cancer where an underlying liver disease was suspected. The third PSC patient reported her mother having chronic liver inflammation, however, a liver biopsy has not been performed. The mother is 67 years old, suffers from diabetes and has no inflammatory bowel disease or diarrhoea Comparison of autoimmune diseases among firstdegree to patients with inflammatory bowel disease with and without PSC We compared the frequency of first-degree with autoimmune diseases among patients (nz126) and controls (nz126) (Table 3). No differences of the frequency of with autoimmune diseases outside the liver were found between the two groups. Eleven patients had a first-degree relative with liver disease compared to four in the non-psc IBD patients. The liver disease in the four non-psc IBD patients was unspecified liver cirrhosis in two, liver cysts in one and unspecified hepatitis in one. Five of the 126 PSC patients with IBD had a first-degree relative (PZ0.06) and one had autoimmune hepatitis Family history of autoimmune liver disease/ibd and outcome of PSC We also compared PSC patients with (nz22) and without (nz122) a first-degree relative with autoimmune liver disease/ibd. This was done in order to investigate if a history of autoimmune liver disease/ibd may influence the presentation or outcome of PSC. No difference between these groups was found in distribution of PSC, presence of symptoms, IBD or age at onset of PSC. Table 3 Comparison of the frequency of first-degree with autoimmune disease to IBD patients with and without PSC firstdegree with: PSC and IBD (nz126) IBD without PSC (nz126) P-value Autoimmune 37 b 38 b n.s. diseases a Rheumatoid n.s. arthritis Thyroid disease n.s. Diabetes n.s. Inflammatory 13(9) 8(7) n.s. bowel disease (ulcerative colitis) PSC a Rheumatoid arthritis, diabetes, thyroid disease, IBD, autoimmune liver disease. b Some patients suffered from more than one autoimmune liver disease. 4. Discussion In this study of 145 patients, five cases of PSC were found among first-degree (3.4%). Previous case reports have shown that familial occurrence of PSC exists and Quigley et al. reported already in 1983 six cases in three different families [7]. However, the familial occurrence of PSC and IBD in a large group of PSC patients has until now not been evaluated. The point prevalence of PSC in the general population in Oslo, Norway is 8.5 per 100,000 inhabitants [13]. In our study, the prevalence of PSC among first-degree (parents, siblings and children) was 0.7%. This represents a nearly 100-fold increased risk for first-degree to develop PSC as compared to general population. In all five the diagnosis was verified and fulfilled the diagnostic criteria for PSC. The risk for development of PSC in children to patients is today difficult to evaluate and the prevalence of 0.7% among first-degree may be an underestimation. PSC is a young disease and the diagnosis was not commonly identified until the more wide spread use of endoscopic retrograde cholangiography in the late 1970s. In addition, effective treatment with liver transplantation was not available until the mid 1980s in Sweden. The onset of PSC is between the age of years and not many of the PSC patients alive today have children who are old enough to have developed PSC. In our study no index case had a child and the mean age of the patients was 47 years. However, one of our younger index patients has a mother who developed PSC more than 10 years after her daughter. The risk for children to PSC patients to develop IBD and PSC has to be further evaluated in the future. In the present study, there was no difference in the frequency of first-degree to PSC patients and controls to have IBD or other extra hepatic autoimmune diseases. This is probably explained by the high prevalence of autoimmune disorders in IBD patients. In the present study the non-psc IBD patients had a relative with IBD in 6% (8/126) cases. This finding is in line with previous studies of the prevalence of IBD among first-degree of patients with IBD [14,15]. Having a relative with IBD is an important risk factor for development of this disease [15]. The high prevalence of PSC among firstdegree to PSC patients may not be caused by the close association between PSC and IBD, but may rather be an effect of PSC itself. Among the 19 PSC patients without an associated IBD, 26% had a first-degree relative with IBD. This was higher than among PSC patients with IBD (9%) (P!0.05). This finding further strengthens the close association between PSC and IBD and suggests that PSC patients without IBD are not a separate entity from PSC patients with IBD. In the present study, a large cohort of PSC and IBD patients have been included and all patients completed the questionnaire. The major drawback with the study is the use

4 A. Bergquist et al. / Journal of Hepatology 42 (2005) of a questionnaire leading to a risk of underestimation of prevalence, since the patients may not have complete information about autoimmune diseases in all their. However, the same questionnaire was used in all patients and controls and since also the controls have a chronic autoimmune disease it seems less plausible that PSC patients should be more alert to the presence of autoimmune diseases among their. The fact that all patients included in the study answered the questionnaire speaks in favour of the great interest all these patients have concerning issues related to the cause of their disease. The controls in this study were IBD patients without PSC and it could be argued that these patients could have an undiagnosed PSC, since it has been described that patients can have normal liver function tests. In order to try to minimise this bias all IBD patients had repeated measurements with liver functions test that showed complete normal levels. Moreover, they did not have any symptoms of PSC probably leading to a minimal risk of missing the PSC diagnosis. In primary biliary cirrhosis (PBC), another chronic cholestatic autoimmune liver disease affecting only the small bile ducts, the familial occurrence and risk of firstdegree to develop PBC has been evaluated in several studies. In a recent study by Jones et al. including 160 PBC patients, a positive family history of PBC was found in 10 cases (6.4%) [16]. The prevalence of PBC among first-degree to patients with PBC was 0.72% and the prevalence for siblings to patients with PBC was 0.41%. This can be compared with the similar prevalence of 0.7% among first-degree to PSC patients in the present study. In the study by Jones it was found that the highest prevalence of PBC was found in daughters of patients, the prevalence being 1.2%. They concluded that suspicion of disease, therefore, should be highest in this group of. In our study siblings to patients seem to be at particular risk with a prevalence of PSC of 1.5%. Tsuji et al., studied 156 Japanese patients with PBC and found a 5.4% prevalence of PBC among first-degree. In that study it was also found that the age at onset of PBC in the second generation was lower than the median disease onset of PBC, 33 and 56 years of age, respectively. Whether age of onset for PSC patients in the second generation is lower cannot be evaluated in the present study. However, we found one parent-child association, both mother and daughter having PSC. The child was the index case and she developed PSC at 15 years of age, which is an early onset compared to the majority of PSC patients (32 42 years) [3]. A major strength of the present study was the fact that all patients included in the study answered the questionnaire. Moreover, we were able to confirm the PSC diagnosis in all five that were reported to have PSC. However, the prevalence of PSC among first-degree may be underestimated since three patients had with unspecified chronic liver disease, which could have been an undiagnosed PSC. Data concerning the cause of the liver disease in these patients unfortunately cannot be found. The high age at death in two of the, 92 and 77 years, respectively, and no inflammatory bowel disease in the third relative speaks against an underlying PSC in these. The performance of studies of PSC at a tertiary referral centre like ours, with a transplant unit, always harbours the risk of selection bias. A greater number of patients with severe disease are likely to be included. The general characteristics of the PSC patients in the present study concerning age at onset of PSC, association with IBD however, is similar to other studies although the number of patients that have been liver transplanted is high [3,4]. In conclusion, first-degree to patients have a 0.7% prevalence of PSC and, therefore, seem to run a nearly 100-fold increased risk of developing PSC compared with the general population. Siblings to PSC patients seem to run an even higher risk with a prevalence of PSC of 1.5%. Acknowledgements We acknowledge the Knut and Alice Wallenberg Foundation and the excellent secretarial assistance by Birgitta Lundh-Pernås is highly appreciated. References [1] Olerup O, Olsson R, Hultcrantz R. HLA-DR and HLA-DQ are not markers for rapid disease progression in primary sclerosing cholangitis. Gastroenterology 1995;108: [2] Xu B, Broomè U, Ericzon B, Sumitran-Holgersson S. High frequency of autoantibodies in patients with primary sclerosing cholangitis that bind epithelial cells and induce expression of CD44 and production of interleukin 6. Gut 2002;51: [3] Broomé U, Olsson R, Lööf L, Bodemar G, Hultcrantz R, Danielsson A, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38: [4] Schrumpf E, Abdelnoor M, Fausa O, Elgjo K, Jenssen E, Kolmannskog F. Risk factors in primary sclerosing cholangitis. J Hepatol 1994;21:1061. [5] Saarinen S, Olerup O, Broomé U. Increased frequency of autoimmune diseases in patients with primary sclerosing cholangitis. Am J Gastroenterol 2000;95: [6] Donaldsson P, Farrant J, Wilkinsson Mea. Dual association of HLA DR2 and DR3 with primary sclerosing cholangitis. Hepatology 1991; 13: [7] Quigley E, LaRusso N, Ludwig R, Birnie G, Watkinson G. Familial occurrence of primary sclerosing cholangitis and ulcerative colitis. Gastroenterology 1983;85: [8] Habior A, Rawa T, Orlowska J, Sankowska M, Lewartowska A, Tilszer A, et al. Asssociation of primary sclerosing cholangitis, ulcerative colitis and coeliac disease in female siblings. Eur J Gastroenterol Hepatol 2002;14: [9] Jorges AD, Esley C, Ahumada J. Family incidence of primary sclerosing cholangitis associated with immunologic disease. Endoscopy 1987;19:

5 256 A. Bergquist et al. / Journal of Hepatology 42 (2005) [10] Talwalkar J, Lindor K. Natural history and prognostic models in primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2001;15: [11] Broomé U, Glaumann H, LindströmE,Lööf L, Almer A, Prytz H, et al. Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC). J Hepatol 2002;36: [12] Evans J, Acheson E. An epidemiological study of ulcerative colitis and regional enteritis in the Oxford area. Gut 1965;6: [13] Boberg K, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol 1998;33: [14] Monsen U, Bernell O, Hellers G. Prevalence of inflammatory bowel disease among of patients with Crohn s disease. Scand J Gastroeneterol 1991;26: [15] Hugot J, Zouali H, Lesage S, Thomas G. Etiology of the inflammatory bowel diseases. Int J Colorectal Dis 1999;14:2 9. [16] Jones E, Watt F, Metcalf J, Bassendine M, James O. Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol 1999;30: