Gastroenterology. in Nuremberg. Falk Lunchtime Symposium: Update on Autoimmune Liver Diseases

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1 Nuremberg (Germany), September 12, 2013 Gastroenterology in Nuremberg Falk Lunchtime Symposium: Update on Autoimmune Liver Diseases on the occasion of the Annual Meeting of the Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (German Society for Digestive and Metabolic Diseases, DGVS), Visceral Medicine 2013 Scientific Organization Speakers Prof. Dr. G. Gerken University Medical Center Essen (Germany) Prof. Dr. C. Schramm Prof. Dr. C. P. Strassburg PD Dr. K. Herzer University Medical Center University Medical Center University Medical Center Eppendorf, Hamburg Bonn (Germany) Essen (Germany) (Germany) 1

2 Falk Symposia and Workshops Falk Workshop Pathophysiology and Treatment of Cholangiocarcinoma Tübingen, Germany January 23 24, 2014 Falk Symposium 192 IBD 2014: Thinking Out of the Box Paris, France May 30 31, 2014 Falk Symposium 193 Celiac Disease and Other Small Bowel Disorders Amsterdam, The Netherlands September 5 6, 2014 VII Falk Gastro-Conference Freiburg, Germany October 8 11, 2014 Falk Symposium 194 (Part I) XXIII International Bile Acid Meeting Bile Acids as Signal Integrators and Metabolic Modulators October 8 9, 2014 Falk Workshop The Challenge of Drug-Induced Liver Injury (DILI) October 9, 2014 Falk Symposium 195 (Part II) Challenges and Management of Liver Cirrhosis October 10 11, 2014 Congress Department Tel.: +49 (0)761/ Fax: +49 (0)761/ symposia@falkfoundation.de

3 Falk Lunchtime Symposium "Update on Autoimmune Liver Diseases" Liver transplantation frequently an outcome of autoimmune liver disease Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) are frequent reasons for a pending liver transplantation. A Falk Foundation lunchtime symposium on the occasion of the Annual Meeting of the Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (German Society for Digestive and Metabolic Diseases, DGVS), Visceral Medicine 2013 in Nuremberg included a discussion of the salient points in diagnosing and treating these diseases to avoid complications up to and including the need for organ transplantation. The discussion also covered the organ allocation procedure and important considerations for patient aftercare if a liver transplantation is indicated. According to Prof. Dr. G. Gerken, Essen, the importance of autoimmune diseases of the liver is often underestimated, and the diseases are also often underdiagnosed. Diseases such as autoimmune hepatitis (AIH), PBC, and PSC are associated with a high risk of chronic progressive liver damage, development of liver cirrhosis, hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCC). Diagnosis and treatment of autoimmune liver diseases Prof. Dr. C. Schramm, Hamburg, spoke about the underlying pathophysiology of the respective diseases, their cardinal symptoms, how the diseases differ from one another, and relevant considerations during diagnosis. Treatment of the various autoimmune diseases was the topic of Prof. Dr. C.P. Strassburg, Bonn. The hepatologist explained why ursodeoxycholic acid is the standard treatment for PBC, the current strategies for treating PSC, and how to go about inducing and maintaining remission in patients with AIH. Focus on liver transplantation Liver transplantation due to autoimmune liver diseases was a focus of the symposium. When it should be considered and how to proceed was outlined by PD Dr. K. Herzer, Essen. She also stressed the importance of regular and standardized aftercare, which must take place in a context of close cooperation between the transplant center and the patient's family physician and gastroenterologist. Following the intervention, everything must be done to prevent organ rejection and steps taken to prevent the recurrence of the primary disease. If the primary disease does recur, treatment is virtually the same as that applied prior to transplantation. 3

4 Falk Lunchtime Symposium "Update on Autoimmune Liver Diseases" PBC and PSC early consideration of cholestatic liver disease Both primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are associated with an increased risk of developing cirrhosis of the liver and liver cell carcinoma. Therefore, if the appropriate clinical symptoms are present, it is important to consider autoimmune liver disease at an early stage in order to make an effective early treatment possible. According to Prof. Dr. C. Schramm, Hamburg, primary biliary cirrhosis (PBC) is the most common autoimmune liver disease. The disease is characterized by chronic inflammation of the small bile duct, fibrotic changes, and ductopenia. Almost 90% of affected patients are female, the disease generally manifests itself during middle age, and further progression can lead to cirrhosis of the liver. But do not disregard PBC in male patients Even though the incidence is predominantly in females, one mustn't forget that the disease can also occur in males, a group in which it is often overlooked. "However, the diagnosis is important, since PBC is often more aggressive in males than in females," stressed Prof. Schramm. Fig. 1: Primary biliary cirrhosis: ERC findings 4

5 In addition, males respond less well to the medication and they develop cirrhosis of the liver in disproportionate numbers. PBC pathogenesis is multifactorial. After sex and age, genetic predisposition and epigenetic phenomena as well as infections and overall environmental factors also play a role. The interaction of the pathogenetic factors leads to a gradual loss of tolerance of mitochondrial antigens in biliary epithelial cells and to a cellular and humoral immune reaction to antigens of the pyruvate dehydrogenase complex of the inner mitochondrial membrane (PDC-E2). Diagnosis is based on evidence of antimitochondrial antibodies, which are present in 95% of patients. If such is the case along with the presence of elevated cholestatic liver values, a biopsy is not absolutely necessary to confirm the diagnosis, but it can help determine the level of inflammatory activity of the disease. PBC must be considered in the case of symptoms such as tiredness and fatigue, which can present at any age as well as pruritus and sicca syndrome. PSC often associated with ulcerative colitis Primary sclerosing cholangitis (PSC) is a chronic fibrosing inflammatory disease of the intra- and extrahepatic bile ducts. As a rule, the disease is progressive, resulting in cirrhosis of the liver after years. The disease affects males to females in a ratio of 3:2, with the average age of onset being between years. There is a striking association with inflammatory bowel disease (IBD): 60 80% of PSC patients also exhibit IBD, usually ulcerative colitis. Moreover, there is an elevated risk of developing hepatobiliary cancer, particularly cholangiocarcinoma. Fig. 2: Primary sclerosing cholangitis: ERC findings The pathogenesis is multifactorial, but ultimately not well understood. It is assumed that the disease develops from a genetic susceptibility, which is presumably induced by external triggers. Triggers may include a mucosal barrier disorder as well as toxic bile acids, which can support the chronic inflammation. Diagnosis of PSC is often difficult, according to Prof. Schramm. It is based on an MRCP or ERCP, with histology being optional. The liver histology is primarily important for diagnosing so-called "small duct PSC", which exhibits a normal cholangiogram. Additionally, an overlap syndrome with autoimmune hepatitis can only be diagnosed with the help of liver histology. "PSC should be considered in particular for patients with inflammatory bowel disease also presenting elevated cholestatic liver readings," says Prof. Schramm. 5

6 Falk Lunchtime Symposium "Update on Autoimmune Liver Disease" Autoimmune liver disease: proven and new treatment concepts Ursodeoxycholic acid is a good therapeutic option for primary biliary cirrhosis (PBC), and there is hope for new therapeutic innovations in the foreseeable future. The situation is more difficult with primary sclerosing cholangitis (PSC), where there is still a need for therapeutic advances. Good treatment options exist for autoimmune hepatitis, for which the primary concern is minimizing the side effects of steroids. Even though PBC is an immune-mediated disease, immunosuppressants are not an effective therapy. According to Prof. C.P. Strassburg, Bonn, the standard therapy consists rather of administering ursodeoxycholic acid (UDCA). Treatment using this bile acid leads to a change in the bile acid pool and displacement of toxic bile acids. Survival benefits for patients responding to ursodeoxycholic acid Patient response to the treatment is of prognostic importance. A significant downturn in cholestatic liver readings is correlated with better survival rates. Normalization of albumin and bilirubin under the treatment also indicates a favorable prognosis. "Response to treatment with ursodeoxycholic acid helps us determine the prognosis for survival Fig. 3: Structural formula of ursodeoxycholic acid (UDCA) 6

7 and the likelihood of a need for organ transplantation," says Prof. Strassburg. He suggested another relatively new therapeutic approach for PBC: a combination of UDCA and the locally active steroid, budesonide*, which can also apparently induce the expression of bile acid transporters. A further therapy option might appear soon in the form of a chemically modified bile acid called nor-ursodeoxycholic acid (nor-udca). Treatment with nor-udca leads to a protective bicarbonate-rich bile and likewise facilitates favorable therapeutic effects via modification of hepatobiliary transporter proteins. The microbiological situation must also be borne in mind," admonished Prof. Strassburg. In most cases, treatment can be optimized by consistent bacterial diagnosis. Fig. 4: Complete remission (ALT and AST in the normal range without steroid-specific side effects) under budesonide and prednisone (in each case in combination with azathioprine) after 6 months Manns et al., Gastroenterology. 2010;139: Fig. 5: Decline in steroid-specific side effects after switching from prednisone to budesonide (in each case in combination with azathioprine) PSC When should a liver transplantation be considered? Ursodeoxycholic acid** should also be considered as a viable option for treating PSC; the use of bile acids is one possible treatment option according to the EASL guidelines, but it is not explicitly recommended. However, clinical experience also reveals better prognosis results for patients exhibiting biochemical response. Treating PSC also comprises of an antibiotic treatment for bacterial cholangitis that should be accompanied by microbiological bile analysis, calculated endotherapy and, in the future, even treatment with modified bile acid, nor-udca. According to Prof. Strassburg, patients in an advanced stage of PSC are candidates for a liver transplantation. PSC qualifies as a "Standard Exception listing" (SE listing) if the patient presents a relevant weight loss, if dominant stenoses are present or bacterial cholangitis is detectable without intervention, according to the latest revision of the allocations criteria during the past year. Budesonide and autoimmune hepatitis high efficacy with reduced side effects Prof. Strassburg asserts that the presence of autoimmune hepatitis along with elevated liver values is a fundamental indication for treatment. The goal is to induce and maintain a remission. Options to be considered include monotherapy with prednisone or combination therapy with azathioprine. Nearly 80% of patients respond to this therapeutic strategy. Cyclosporine and mycophenolate are alternative therapies for the remainder of the patients. A prospective randomized multicenter double-blind study has now shown that the rate of side effects can be sharply reduced by using budesonide, a steroid with high first-pass metabolism compared with prednisone. Both compounds were used in combination with azathioprine. While the responses were similar, steroid-specific side effects such as acne, buffalo hump and moon face have a significantly lower incidence under budesonide than under prednisone. Complete remission (normalization of the transaminases without steroidspecific side effects), was achieved at a highly significantly increased frequency under budesonide than under prednisone. This is a particular advantage in treatments to maintain remission, where the steroid must usually be administered long-term. The study also shows that side effects were significantly reduced by switching from prednisone to budesonide (Figs. 4 and 5). "Budesonide was shown to be effective in inducing remission in untreated patients and also for treating recurring AIH," stressed Prof. Strassburg. * Budesonide is not approved for the treatment of PBC. ** Ursodeoxycholic acid is not approved for the treatment of PSC. 7

8 Falk Lunchtime Symposium "Update on Autoimmune Liver Disease" PBC, PSC and AIH Don't neglect aftercare following liver transplantation Liver transplantation is often the last resort when the progression of an autoimmune liver disease such as PBC, PSC, or AIH cannot be halted. Systematic aftercare is essential after the transplantation. All measures must be taken to avoid organ rejection. Should the disease re-occur, treatment proceeds according to the same criteria used for the primary underlying disease. Viral and nutritional liver diseases remain the most common diseases leading to a liver transplantation. However, autoimmune liver diseases already account for a significant proportion, reported PD Dr. K. Herzer, Essen. Thus, 13% of liver transplantations are currently caused by AIH, and when the latter is considered together with PBC and PSC, the proportion of liver transplantations seen at the Essen transplant center due to autoimmune liver disease is close to 20%. "Standard Exceptions", an additional allocation system Patients having a MELD score (Model for End-stage Liver Disease) of 15 can expect a survival benefit and are therefore candidates for listing. In addition, patients with a MELD score of 10 and those with terminal liver disease as well as complications such as a new occurrence of ascites, encephalopathy, or a hepatorenal syndrome should be referred to the transplant center in order to not miss the best time for listing, stressed Dr. Herzer. PSC and some other diseases are not adequately indicated by the MELD score alone. This led to the introduction of the "Standard Exceptions" allocation system, which can assign points in a way that is independent of laboratory results. "This system has given patients with PSC a fair chance of receiving an organ," the physician explained. The 5-year post-intervention survival rate is good compared to other indications: 80 90% for PBC, 75 80% for PSC, and 65 72% for AIH. Be prepared for a recurrence of the underlying disease We must always be ready to treat a recurrence of the underlying disease after the transplantation. According to Dr. Herzer, diagnosing and treating the recurrence after liver transplantation represents a "sizable challenge". Recidivism rates of 18 30% for PBC, 11% for PSC, and 22% for AIH have been reported. Overall, recidivism is responsible for a second organ transplantation being required in 10 15% of patients. Furthermore, there is an elevated risk of transplant rejection in transplants performed as a result of autoimmune liver disease, especially in the case of PSC, for which nearly 50% of patients experience one or more rejection episodes during the first months after the transplantation. "An acute rejection entails an elevated risk of a recurrence of the disease," said the physician from Essen. 8

9 Severe inflammation Pseudopolyps Fig. 6: Chronic ulcerative colitis Mitigate organ rejection through systematic aftercare Recurrence is more common with AIH than with cholestatic liver diseases, "but the recurring disease is easier to treat," according to Dr. Herzer. Standard treatment involves the use of steroids, the active substance budesonide being the treatment of choice since the risk of side effects with this locally acting steroid is markedly lower than with systemic corticosteroids. "We can usually achieve stabilization of the clinical picture using budesonide," stated Dr. Herzer. However, when there is exacerbation of recurrent AIH, administration of azathioprine should also be considered and, if required, a switch of immunosuppressants, keeping a retransplantation as last resort. Transplant rejections therefore must be recognized earlier and, according to Dr. Herzer, "be treated vigorously" in order to respond to the potential recurrence of the disease. Because of the elevated risk of simultaneous inflammatory bowel disease, which is seen frequently with PSC, regular colonoscopies are an invaluable part of aftercare. Should the autoimmune liver disease recur, the patient's treatment is essentially the same as that of the first occurrence. This means that administration of ursodeoxycholic acid (UDCA) is indicated for PBC, and this bile acid is also routinely given for PSC* in Essen. Additionally, dominant strictures are treated endoscopically. This treatment regime mitigates recurrence, and 3-year and 5-year survival rates are considerably improved. * Ursodeoxycholic acid is not approved for the treatment of PSC. Post-operative transplant graft complications are detected by signs of transplant graft dysfunction, including increased liver enzymes, reduction in bile production and drop in hepatic synthetic parameters. The dysfunction may be of vascular, biliary or parenchymal origin. The work-up of transplant graft dysfunction is based on the following algorithm: Fig. 7: Postoperative complications Transplant graft dysfunction Doppler ultrasound Suspicion of vascular complications Bile ducts/vessels unremarkable Suspicion of bile duct complications Angiography, angio-ct/mri Sonographically guided ERC, PTC, MRCP puncture biopsy of the liver Ischemia/Reperfusion damage CMV, EBV, HCV, HBV HSV, VZV, HEV Viral and fungal infections Rejection ERC: Endoscopic retrograde cholangiography PTC: Percutaneous transhepatic cholangiography MRCP: Magnetic resonance cholangiopancreaticography 9

10 Interview with PD Dr. Kerstin Herzer, Essen Liver transplantation: Postoperative care is not yet standardized Dr. Herzer, what are the problems and shortfalls of aftercare of liver transplantation patients? To date, the main problem has been the lack of evidence-based standardized aftercare. While we do have clear guidelines on how to treat certain illnesses, such standards are missing with respect to aftercare. As a result, there is no uniform standard covering all of Germany. To a very large extent, the individual transplant centers define their own aftercare procedures. Even though the individual 10 centers follow the same procedures in some situations, there are others in which their procedures are fundamentally different. It would be desirable for aftercare to be standardized and recommended guidelines to be developed. Why would standardized aftercare be important? Aftercare that is based on evidence and best practice can contribute significantly to reducing complications. This is of immense importance for the long-term success of the transplant, and it can help avoid the need for a repeat transplant. This is an enormously important aspect, both for the patient's quality of life and in view of the organ shortage. What are the most important components of aftercare? The patients must be monitored with regular follow-up examinations to check their health status. These include regular laboratory tests and other examinations that we use to clarify whether, for example, a transplant is being rejected, or whether the underlying disease is recurring in the donated organ, or whether there are other imminent complications. The patients are exposed to various risks after transplantation. Besides a recurrence of the underlying disease and transplant rejection, they are susceptible, for example, to infections that can arise after treatment with immunosuppressive drugs, which can also have toxic side effects. There is also an elevated risk of developing de-novo tumors following long-term immune system suppression. How do you treat a recurrence of the underlying disease? In such cases we treat patients by essentially following the guidelines provided for the underlying disease, such as for PBC, PSC, or AIH. For example, we treat cholestatic liver disease* with ursodeoxycholic acid, which is commonly used to treat the primary disease. And in addition to the use of steroids, changing the immunosuppressive drug regime helps in the case of recurring AIH. * Ursodeoxycholic acid is not approved for the treatment of PSC.

11 What examinations are required and how often? The transplant centers generally assume responsibility for this, although this is not governed by any clear provisions. We think it is right that such care has become located in the specialty centers. The examinations are certainly elaborate at times and a certain level of expertise is required to recognize and respond to the threat of imminent complications in a reliable and timely manner to allow them to be adequately addressed. But it is also important to us to involve the family doctor and the local gastroenterologists in aftercare because they are usually the first contact for the patient and as a rule easier to reach. Aftercare Following Liver Transplantation Pharmacological Therapy Complications Lifestyle During the first months after a transplantation, we monitor the laboratory results and the immunosuppression picture every week or every two weeks. After 3 6 months, we switch to monthly checkups. In stable situations, a quarterly checkup schedule suffices, in our opinion. We perform a duplex ultrasound of the transplanted organ semi-annually and a fibroscan once per year. We also feel a bone density scan is necessary once per year since bone metabolism is often already reduced in patients with liver disease, and this can become worse under treatment with immunosuppressants. In addition, we arrange for consultation with a specialist, which could be an annual dermatology examination to screen for tumors, for example. What form does this cooperation take? The family doctor and the local gastroenterologist are the first point of contact if the patient has concerns. They can also arrange laboratory tests and follow-ups. When complications arising from the transplant are suspected, the doctor should contact the center and share the relevant findings to allow a detailed assessment to take place. From then on, follow-up care ought to be monitored in the center in close cooperation with the family doctor and gastroenterologist. Dr. Herzer, thank you very much for the interview. Recommended Practices for Cooperation Between the Primary Care Provider and the Transplant Center Kerstin Herzer, MD, Associate Professor of Medicine Guido Gerken, MD, Professor of Medicine University Hospital of Essen (Germany) New practice guidelines In Germany, there are no overarching guidelines for aftercare following a liver transplant. The new 35-page booklet entitled, "Aftercare Following Liver Transplantation by PD Dr. K. Herzer and Prof. Dr. G. Gerken can serve as a guideline for the cooperation of family doctors and transplant centers. This brochure can be ordered free of charge from Falk Foundation e.v. or the local Falk partner. We feel a colonoscopy is needed every three years because it has been shown that there is an increased risk of developing colorectal cancer under immunosuppression. What area is responsible for aftercare? Publisher FALK FOUNDATION e.v. Leinenweberstr Freiburg Germany Falk Foundation e.v. All rights reserved. Text Christine Vetter (Medical Journalist) eickhoff kommunikation GmbH Probsteigasse Cologne (Germany) 11

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