U. Beuers

The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes

Aliment Pharmacol Ther 2011; 34: 335–343

Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands

Abstract Background and aims. Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). Methods. Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. Results. The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3–19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5–2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1–44 years). Familial occurrence was reported in three cases. Conclusion. This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.

Mycophenolate mofetil: role in autoimmune hepatitis and overlap syndromes.

Aliment Pharmacol Ther 2011; 34: 335–343

Modern work-up and extended resection in perihilar cholangiocarcinoma: the AMC experience

AimPerihilar cholangiocarcinoma (PHC) is a challenging disease and requires aggressive surgical treatment in order to achieve curation. The assessment and work-up of patients with presumed PHC is multidisciplinary, complex and requires extensive experience. The aim of this paper is to review current aspects of diagnosis, preoperative work-up and extended resection in patients with PHC from the perspective of our own institutional experience with this complex tumor.MethodsWe provided a review of applied modalities in the diagnosis and work-up of PHC according to current literature. All patients with presumed PHC in our center between 2000 and 2016 were identified and described. The types of resection, surgical techniques and outcomes were analyzed.Results and conclusionUpcoming diagnostic modalities such as Spyglass and combinations of serum biomarkers and molecular markers have potential to decrease the rate of misdiagnosis of benign, inflammatory disease. Assessment of liver function with hepatobiliary scintigraphy provides better information on the future remnant liver (FRL) than volume alone. The selective use of staging laparoscopy is advisable to avoid futile laparotomies. In patients requiring extended resection, selective preoperative biliary drainage is mandatory in cholangitis and when FRL is small (<u200950%). Preoperative portal vein embolization (PVE) is used when FRL volume is less than 40% and optionally includes the left portal vein branches to segment 4. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as alternative to PVE is not recommended in PHC. N2 positive lymph nodes preclude long-term survival. The benefit of unconditional en bloc resection of the portal vein bifurcation is uncertain. Along these lines, an aggressive surgical approach encompassing extended liver resection including segment 1, regional lymphadenectomy and conditional portal venous resection translates into favorable long-term survival.

[Cholestatic pruritus : new insights into pathophysiology and current treatment].

Pruritus is a common symptom of hepatobiliary disorders and may considerably diminish quality of life. Cholestatic pruritus exerts a circadian rhythm and is typically most severe in the evening hours and early at night. Itching is reported often to be most intense at the palms and the soles, but may also be generalized. The pathophysiological mechanisms of cholestatic pruritus have not been completely clarified. In the past, bile salts, histamine, progesterone metabolites and opioids have been discussed as potential causal substances; a correlation with itch intensity could never be proven. The enzyme autotaxin, which releases lysophosphatidic acid, has recently been identified as potential cholestatic pruritogen. Treatment aims to bind pruritogens in the gut lumen by resins such as cholestyramine, to modulate pruritogen metabolism by rifampicin and to influence central itch signaling by µ-opioid antagonists and selective serotonin re-uptake inhibitors. In cases of refractory pruritus experimental treatment options such as UV-therapy, extracorporeal albumin dialysis and nasobiliary drainage may be considered.ZusammenfassungPruritus ist ein häufiges Symptom cholestatischer Leber- und Gallenwegserkrankungen und kann die Lebensqualität der betroffenen Patienten ernsthaft einschränken. Cholestatischer Pruritus weist einen zirkadianen Rhythmus mit Maximum am Abend oder in den frühen Nachtstunden auf. Häufig ist der Pruritus am intensivsten an Handinnenflächen und Fußsohlen, er kann aber auch generalisiert auftreten. Die Pathogenese des cholestatischen Pruritus ist noch nicht eindeutig geklärt. In der Vergangenheit wurden Gallensalze, Histamin, Progesteronmetabolite und Opioide als mögliche auslösende Substanzen diskutiert, ohne dass jemals eine Korrelation mit der Pruritusintensität aufgezeigt werden konnte. Das Enzym Autotaxin, das Lysophosphatidsäure freisetzt, wurde kürzlich als mögliches cholestatisches Pruritogen identifiziert. Therapeutisch wird versucht, Pruritogene im Darmlumen mit Austauscherharzen zu binden, den Pruritogenmetabolismus durch Rifampicin zu modulieren und die Pruritusweiterleitung im zentralen Nervensystem durch μ-Antagonisten und selektive Serotoninwiederaufnahmehemmer zu beeinflussen. Bei therapieresistentem Pruritus können experimentelle Behandlungen wie UV-Bestrahlung, extrakorporale Albumindialyse und nasobiliäre Drainage erwogen werden.AbstractPruritus is a common symptom of hepatobiliary disorders and may considerably diminish quality of life. Cholestatic pruritus exerts a circadian rhythm and is typically most severe in the evening hours and early at night. Itching is reported often to be most intense at the palms and the soles, but may also be generalized. The pathophysiological mechanisms of cholestatic pruritus have not been completely clarified. In the past, bile salts, histamine, progesterone metabolites and opioids have been discussed as potential causal substances; a correlation with itch intensity could never be proven. The enzyme autotaxin, which releases lysophosphatidic acid, has recently been identified as potential cholestatic pruritogen. Treatment aims to bind pruritogens in the gut lumen by resins such as cholestyramine, to modulate pruritogen metabolism by rifampicin and to influence central itch signaling by µ-opioid antagonists and selective serotonin re-uptake inhibitors. In cases of refractory pruritus experimental treatment options such as UV-therapy, extracorporeal albumin dialysis and nasobiliary drainage may be considered.

5 Bestaat er een relatie tussen pancreatitis en prostatitis

Introductie IgG4-gerelateerde ziekte (IgG4-RD) is een zeldzame systeemziekte die wordt gekarakteriseerd door een verhoogde waarde van IgG4 in het serum, toegenomen IgG4-positieve plasmacellen in het weefsel en een goede respons op prednisonbehandeling. De meest voorkomende uiting is de auto-immuun pancreatitis (AIP). Doel van deze studie was het evalueren van het voorkomen en de histopathologische karakteristieken van IgG4-gerelateerde prostaataandoening bij patiënten met de diagnose AIP.

P658 Colorectal cancer in primary sclerosing cholangitis: the importance of surveillance

Background: Crohn’s disease (CD) and ulcerative colitis (UC) are major causes of morbidity and a growing burden to the Austrian healthcare system. Contact points and specialized facilities are a fundamental basis for speedy diagnosis and fast appropriate treatment. The objective of our study was to assess the number of specialized facilities available for patients suffering from CD or UC and compare their number to the respective prevalence on a per-county level. Moreover, we compared the prevalenceadjusted numbers to the inflammatory rheumatic diseases to assess possible differences in quality of care. Methods: We conducted desk research on the epidemiological parameters of incidence and prevalence of both inflammatory diseases of the bowel (CD and CU) and inflammatory diseases of the bones and joints (rheumatic arthritis, RA; psoriatic arthritis, PsA; ankylosing spondylitis, AS) in Austria. We adjusted the data to exclude comorbidities and when necessary adjusted international data using data from the Austrian Central Statistics Office. To obtain comparable numbers for points of call catering to gastroenterologic and rheumatic patients respectively, we utilized and analyzed data from two novel applications for mobile phones aimed at Austrian patients (RHEUMA AKTIV and DARM AKTIV, respectively). Results: According to our calculations, there are 68,486 patients suffering from UC or CD in Austria. 69 points of call are listed in the DARM AKTIV application. Looking at these numbers in conjunction with the prevalence estimates, this leads to an Austrian average of 993 patients per point of call. However, there are huge disparities across the Austrian counties ranging from 514 patients per point of call in Carinthia to 1,641 patients per point of call in Upper Austria. Taking into account the three most common inflammatory rheumatic diseases RA, PsA and AS, we calculated the total number of Austrians affected to be 108,319. The disparities across the Austrian counties is even more pronounced for the rheumatic diseases and ranges from 764 patients per point of call in Salzburg to 6,922 patients per point of call in Lower Austria. Conclusions: Our study has brought new insights regarding the policy landscape for patients suffering from inflammatory diseases of the bowel or the bones and joints in Austria. We have identified huge disparities across the counties of Austria and conclude that quality of care and access to treatment may also differ across Austria. P658 Colorectal cancer in primary sclerosing cholangitis: the importance of surveillance K. Boonstra1 *, R. Weersma2, K.J. van Erpecum3, E. Rauws1, M. Spanier4, A. Poen5, K. van Nieuwkerk6, J. Drenth7, B. Witteman8, H. Tuynman9, A. Naber10, P. Kingma11, H. van Buuren12, B. van Hoek13, F. Vleggaar3, U. Beuers1, C. Ponsioen1. 1Academic Medical Center Amsterdam, Gastroenterology and Hepatology, Amsterdam, Netherlands, 2University Medical Center Groningen, Gastroenterology and Hepatology, Groningen, Netherlands, 3University Medical Center Utrecht, Gastroenterology and Hepatology, Utrecht, Netherlands, 4Rijnstate Hospital, Gastroenterology and Hepatology, Arnhem, Netherlands, 5Isala Clinics, Gastroenterology and Hepatology, Zwolle, Netherlands, 6VU Medical Center, Gastroenterology and Hepatology, Amsterdam, Netherlands, 7Radboud University Nijmegen Medical Center, Gastroenterology and Hepatology, Nijmegen, Netherlands, 8Gelderse Vallei Hospital, Gastroenterology and Hepatology, Ede, Netherlands, 9Medical Center Alkmaar, Gastroenterology and Hepatology, Alkmaar, Netherlands, 10Tergooiziekenhuizen, Gastroenterology and Hepatology, Hilversum, Netherlands, 11Tergooiziekenhuizen, Gastroenterology and Hepatology, Blaricum, Netherlands, 12Erasmus University Medical Center, Gastroenterology and Hepatology, Rotterdam, Netherlands, 13Leiden University Medical Center, Gastroenterology and Hepatology, Leiden, Netherlands

694 A BILIARY BICARBONATE UMBRELLA PROTECTS HUMAN CHOLANGIOCYTES AND CHOLANGIOCARCINOMA CELLS AGAINST BILE ACID TOXICITY

Human cholangiocytes are physiologically exposed to millimolar concentrations of glycine-conjugated hydrophobic bile salts, which are toxic to other cell types including hepatocytes already in the micromolar range after cell entry. Apolar, protonated bile acids rather than polar, deprotonated bile salts may passively enter cholangiocytes. pKa and biliary pH determine bile acid protonation status in bile. We hypothesize that biliary HCO−3 secretion in humans serves to maintain an alkaline pH near the apical surface of cholangiocytes and fosters deprotonation of apolar bile acids to polar bile salts. This ‘biliary HCO−3-umbrella’ might be a key protective mechanism of human cholangiocytes against glycineconjugated bile acids (Hepatology 2010; 52: 1489). Our aim was to test if toxicity of unconjugated, glycine-conjugated (pKa 4–5) and taurine-conjugated (pKa < 2) bile salts in cholangiocytes is (i) pH-dependent, and (ii) antagonized by anion exchanger 2 (AE2) activity. Methods: Two human cholangiocarcinomaand one human immortalized cholangiocyte cell line were exposed to glycine-, taurine-, and unconjugated chenodeoxycholate (CDC), from 0.1mM to 2.0mM at pH8.0, 7.4, 7.1, 6.7 and 6.4 and after knockdown of AE2 by shRNA. After four hours, cell viability and apoptosis were determined by WST-1 and caspase-3/-7 assays, respectively. Results: In cholangiocarcinoma cells and non-transformed immortalized cholangiocytes, CDCand GCDC-, but not TCDCinduced cholangiocyte toxicity was pH-dependent and increased gradually when pH was lowered from 7.4 to 7.1, 6.7 or 6.4. E.g., in non-transformed cells, at pH 7.4 no bile salt-toxicity was observed while at pH 6.4 0.5mM and 1mM CDC decreased viability by 80.8±5.3 and 83.5±9.7% (p < 0.01, n = 5) and increased caspase-3/-7 activity 9and 27-fold, respectively (p < 0.001, n = 5). Acidification alone had no effect. AE2 knockdown led to 3-fold and 2-fold apoptosis induced by 0.75mM CDC or 2mM GCDC at pH 7.4 (p < 0.01, n = 6). When increasing pH to 8.0 during bile salt exposure, AE2 knockdown cells were rescued from bile salt toxicity. Conclusion: Our data support the protective function of a biliary HCO−3-umbrella against bile acid-induced cholangiocyte injury. AE2 may serve as a key element of this HCO−3-umbrella. Genetic and acquired functional defects of elements of the biliary HCO−3umbrella may contribute to development and progression of cholangiopathies.

Mycophenolate mofetil for patients with autoimmune hepatitis and overlap syndromes : authors' reply

SIRS, Garcia-Buey and Moreno-Otero nicely summarise the literature on mycophenolate mofetil (MM) in autoimmune hepatitis (AIH) and overlap syndromes. The Dutch Autoimmune Hepatitis Group (DAHG) shows that second-line MM induces remission in 67% of patients with AIH and intolerance to azathioprine (AZA). In AIH and AZA nonresponse, remission was achieved with MMF in only 13%, and all deaths, liver transplantations and decompensations of cirrhosis occurred in this group. Therefore, in AIH and AZA-nonresponse other options, including liver transplantation, seem more appropriate. This is consistent with the findings of Hennes et al. nFor all patients with overlap syndromes, MM appears a valuable treatment option. In the DAHG cohort, MM induced remission in 63% and 57%, and nresponse in 15% and 14% after AZA intolerance and nonresponse respectively. Recently, adding MM and budesonide appeared beneficial in primary biliary cirrhosis (PBC) with insufficient response to ursodeoxycholic acid. Further investigations of MM in PBC and overlap seem warranted. nAs first-line therapy for AIH, one randomised controlled study indicates that budesonide with AZA induces more remission with less side-effects than prednisolone with AZA. However, despite the one prospective cohort with MM as first-line therapy in AIH, and the limitations of earlier studies, most evidence for first-line therapy in AIH still is with AZA and prednisolone. We therefore still consider prednisolone with AZA the first-line treatment in AIH and overlap nsyndromes until further randomised studies prove otherwise. In case of steroid side-effects, in the absence of cirrhosis, budesonide could be considered, although a prospective maintenance study against prednisolone is still lacking. nAs second-line therapy in case of AZA-intolerance in AIH, or for all overlap nsyndrome patients, MM with prednisolone appears useful, but not for AIH with AZA nonresponse. In contrast to AZA, MM is contraindicated in pregnancy.

Mycophenolate mofetil for patients with autoimmune hepatitis and overlap syndromes: authors’ reply: Letters to the Editors

SIRS, Garcia-Buey and Moreno-Otero nicely summarise the literature on mycophenolate mofetil (MM) in autoimmune hepatitis (AIH) and overlap syndromes. The Dutch Autoimmune Hepatitis Group (DAHG) shows that second-line MM induces remission in 67% of patients with AIH and intolerance to azathioprine (AZA). In AIH and AZA nonresponse, remission was achieved with MMF in only 13%, and all deaths, liver transplantations and decompensations of cirrhosis occurred in this group. Therefore, in AIH and AZA-nonresponse other options, including liver transplantation, seem more appropriate. This is consistent with the findings of Hennes et al. nFor all patients with overlap syndromes, MM appears a valuable treatment option. In the DAHG cohort, MM induced remission in 63% and 57%, and nresponse in 15% and 14% after AZA intolerance and nonresponse respectively. Recently, adding MM and budesonide appeared beneficial in primary biliary cirrhosis (PBC) with insufficient response to ursodeoxycholic acid. Further investigations of MM in PBC and overlap seem warranted. nAs first-line therapy for AIH, one randomised controlled study indicates that budesonide with AZA induces more remission with less side-effects than prednisolone with AZA. However, despite the one prospective cohort with MM as first-line therapy in AIH, and the limitations of earlier studies, most evidence for first-line therapy in AIH still is with AZA and prednisolone. We therefore still consider prednisolone with AZA the first-line treatment in AIH and overlap nsyndromes until further randomised studies prove otherwise. In case of steroid side-effects, in the absence of cirrhosis, budesonide could be considered, although a prospective maintenance study against prednisolone is still lacking. nAs second-line therapy in case of AZA-intolerance in AIH, or for all overlap nsyndrome patients, MM with prednisolone appears useful, but not for AIH with AZA nonresponse. In contrast to AZA, MM is contraindicated in pregnancy.