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organize

Adriatic Liver Forum:

LIVER DISEASES

CROATIAN SOCIETY OF GASTROENTEROLOGYand UNIVERSITY HOSPITAL DUBRAVA ZAGREB

March 2nd, 2018University Hospital Dubrava

Avenija Gojka Suska 6, Zagreb, Croatia

CHOLESTATIC

organizing committee

faculty

President of Organizing Committee: Ivica Grgurevic

Members of Organizing Committee: Tomislav Bokun, Tonci Bozin, Sanda Mustapic, Vladimir Matic, Rajko Ostojic, Miroslav Simunic

Tomislav Bokun(Zagreb, Croatia)

Neven Ljubicic (Zagreb, Croatia)

Zeljko Puljiz(Split, Croatia)

Davor Radic(Zagreb, Croatia)

Francesca Sa�oti (London, UK)

Nermin Salkic(Tuzla, Bosnia&Herzegovina)

Miroslav Simunic(Split, Croatia)

Lubomir Skladany (Banska Bystrica, Slovakia)

Anita Skrtic (Zagreb, Croatia)

Katja Novak(Ljubljana, SLO)

Mario Tadic(Zagreb, Croatia)

Krzysztof Tomasiewicz(Lublin, Poland)

Emmanouil Tsochatzis(London, UK)

Petra Turcic(Zagreb, Croatia)

Lucija Virovic Jukic(Zagreb, Croatia)

Kresimir Luetic(Zagreb, Croatia)

Aleksandar Manolev(Skopje, Macedonia)

Renata Huzjan-Korunic(Zagreb, Croatia)

Ivana Mikolasevic(Rijeka, Croatia)

Sandra Milic(Rijeka, Croatia)

Tamara Milovanovic Alempijevic(Belgrade, Serbia)

Anna Mrzljak(Zagreb, Croatia)

Maria Papp(Debrecin, Hungary)

Tonci Bozin(Zagreb, Croatia)

Tajana Filipec-Kanizaj(Zagreb, Croatia)

Ivica Grgurevic(Zagreb, Croatia)

Irena Hrstic (Pula, Croatia)

Marko Banic(Zagreb, Croatia)

Peter Jarcuska(Kosice, Slovakia)

Dusko Kardum(Zagreb, Croatia)

Zeljko Krznaric(Zagreb, Croatia)

Milan Kujundzic(Zagreb, Croatia)

Dear colleagues and friends,

Ivica GrgurevicPresident of the Organizing Committee of Adriatic Liver Forum

It is my great pleasure to announce the 4th Adriatic Liver Forum (ALF) conference to be held on 2nd March 2017 in Zagreb, Croatia. The topic of this monothematic conference will be Cholestatic Liver Diseases. As in previous years the conference is co-organised by the University Hospital Dubrava and Croatian Society of Gastroenterology.

Cholestatic liver diseases result from a wide spectrum of aetiologies and have been seen with an increasing frequency in clinical practice. Typical representatives such as Primary biliary cholangi-tis (PBC) and Primary sclerosing cholangitis (PSC) although not that common, seem to be increasing in incidence and prevalence according to recent epidemiological data. PBC and PSC are chronic and often progressive, resulting in end-stage liver disease, its complications and need for liver transplantation. Dilemmas in pathogenesis and di�erential diagnosis, burden of compli-cations and the comprehensive treatment algorithms including personalized approach to current and new treatment options will be discussed in details.

The speakers at the symposium will be eminent experts in the field from Croatia and eight other European countries including Bosnia & Herzegovina, Hungary, Macedonia, Poland, Serbia, Slovakia, Slovenia and United Kingdom. From its foundation (initially under name Seminaria hepatologica) Adriatic Liver Forum has been well accepted by hepatologists from the wider geographic area of Central-South-Eastern Europe as a platform for exchange of knowledge and experience in hepatology in this part of Europe. We are especially happy to see this framework stretching even more as from this year more participants form the Central European region will actively participate at ALF.

By emphasising the need for interdisciplinary approach to liver diseases, we are delighted to announce radiologists, pathologists, clinical pharmacologists and infectologists as the speakers at the symposium together with hepatologists. During the conference hands-on liver ultrasound training on models will be available as well.The scientific value of this event is recognized by the most eminent national and international professional organizations and we are proud to announce that this conference will be held under the high auspices of the Ministry of Health of the Republic of Croatia, and endorsed by European Association for the Study of the Liver (EASL), Croatian Society for Ultrasound in Medicine and Biology of the Croatian Medical Association, University of Zagreb School of Medicine and Faculty of Pharmacy and Biochemistry.Participation at the conference will be accredited according to regulations of Croatian Medical Chamber and all participants will be granted certificate of attendance.

Looking forward to meeting you in Zagreb!

program

09:00-10:30 SESSION 1 Chairmen: Kujundzic M, Simunic M, Ljubicic N

11:00-12:30 SESSION 2 Chairmen: Banic M, Bevanda M, Milic S

10:30-11:00 COFFEE BREAK

08:00-08:30 REGISTRATION

08:30-09:00 Opening ceremony

12:30-14:00 LUNCH

15:30-15:45 COFFEE BREAK

20:00 DINNER

Epidemiology of cholestatic liver diseases / Skladany L (SK)Primary biliary cholangitis (PBC) / Radic D (HR)Primary sclerosing cholangitis (PSC) / Mrzljak A (HR)Clinical features of PBC: real life data from Croatia and Slovenia / Bozin T/Novak K (HR/SLO)

Infective causes of cholestasis / Tomasiewicz K (PL)Nutritional issues in cholestatic liver diseases / Krznaric Z (HR)Pruritus and other complications of cholestasis / Virovic Jukic L (HR)Cholestatic liver diseases in pregnancy / Mikolasevic I (HR)Quality of life in patients with PBC / Alempijevic T (SR)

Patohistology of cholestatic liver diseases / Skrtic A (HR)Imaging: MRI and EUS / Huzjan-Korunic R / Tadic M (HR)Elastography in cholestatic liver diseases / Tsochatzis E (UK)Serological tests for cholestatic liver diseases / Salkic N (BH)Biomarkers of biliary-gut cross-talk in cholestasis / Papp M (HU)

14:00-15:30 SESSION 3 Chairmen: Aralica G, Hrstic I, Luetic K

Predictive factors for the e�ectiveness of UDCA treatment in PBC / Jarcuska P (SK)Novel therapies for cholestatic liver diseases / Grgurevic I (HR)Pharmacological interventions for PBC and PSC: an attempted network meta-analysis / Sa�oti F (UK)Endoscopic management of biliary strictures / Bokun T (HR)Liver transplantation for cholestatic liver diseases / Filipec T (HR)

15:45-17:30 SESSION 4 Chairmen: Kardum D, Puljiz Z, Turcic P

Lunch symposium (13:00-14:00): US course for hepatologists:US in cholestatic liver diseases / Manolev A (MK)Hands-on US (B-mode, elastography, Fibroscan) / Matic V, Mustapic S (HR)

abstractsEPIDEMIOLOGY OF CHOLESTATIC LIVER DISEASES (ChLD)

Lubomir Skladany MD, PhD

HEGITO (Division of Hepatology, Gastroenterology and Liver Transplantation), Department of Internal Medicine II, F.D.Roosevelt University Hospital, Banska Bystrica, Slovakia

Sylvia Drazilova, MD, PhD

Departmentof Internal Medicine, Poprad, Slovakia

Before interpreting data on epidemiology of ChLD (primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), several factors should be considered: case finding and ascertainment (ICD codes, especially in PSC), awareness, evolution and distribution of diagnostic (Dg) and therapeutic tools (AMA1965; ERCP1970‘s; UDCA1980’s; MRCP1990‘s), and computerization. The notion persists about a true time-, and polar-equatorial (North-South) gradient in prevalence of ChLD. Neither proven nor dismissed are links with water sources, waste spotts, IBD and HLA heat maps, seasons, etc.

PBC affects women 10:1, >40 years old (not in children), accounts for up to 2% of cirrhosis deaths, and is 6th indication for LTx in USA. Review of European, North-American, Asian, and Australian papers yielded incidence of 3,3 – 58, and prevalence 19,1 – 402 per 106, respec-tively. Adding other sources, range of prevalence is 6,7 – 940 (141 in Slovakia). First study outside the West showed 7-fold lower prevalence in Israel, followed by even lower one in South-East Asia, and next to nil in Subsaharan Africa. There are significant associations between PBC and ethnic background, family history, HLA patterns, smoking, urinary tract infections, etc; no significant associations have been found for degree of urbanisation, lifestyle, female reproductive characteristics, etc. The uptake of UDCA therapy varied between 37% and 100%.

PSC incidence and prevalence are 0-13, and 0-160 per million (9% of LTx); large- vs small-duct disease is 5-9:1, less in Turkey. IgG4 disease represents < 10%. Median age at Dg was 40 with 2 peaks at 30 and 70, includin 2 yo. Male to female IRR is 1,7; pooled IBD proportion is 68%, less in Asia; overall, racial bias was not confirmed. UDCA uptake is up to 98%. Despite strong link between PSC and IBD, familial clustering is rare. Increase in incidence is suggested but needs confirmation. Cumulative risk of cholangiocarcinoma is 7-20%.

PRIMARY SCLEROSING CHOLANGITIS

Anna Mrzljak, Asst. prof., MD PhD, FEBGH

School of Medicine, University of Zagreb, Department of Gastroenterology, University Hospital Merkur, Zajceva 19, 10000 Zagreb, Croatia; e-mail: [email protected]

Primary sclerosing cholangitis (PSC) is a rare immune-mediated disorder where inflammation and fibrosis lead to multifocal biliary strictures and progressive liver disease. PSC epidemio-logical studies are hampered by the lack of ICD10 code, however report a geographic

gradient towards the South and the East, with 10-fold lower prevalence rates. The initiating factors for PSC still remain obscure, although considerable advances in understanding the genetics of PSC position autoimmune processes central to the pathogenesis of PSC combined with the environmental risks. The role of the gut in PSC development, the interplay between the gut microbiota and host immunology and bile acid physiology are rapidly growing research fields. The current lack of understanding PSC pathogenesis prevents the development of effective therapies.

PSC has a propensity to affect young to middle-aged males, presenting most often as the classical large-duct PSC phenotype. The close association with inflammatory bowel disease is a hallmark of the condition with IBD affecting about three-thirds of patients, most often classified as ulcerative colitis. PSC is associated with a considerable risk of gastrointestinal malignancies, mainly cholangiocarcinoma and colorectal cancer. PSC requires a radiological diagnosis, with the modality of choice now being MRC, whereas liver tests typically show a cholestatic profile. No single biomarker or prognostic score has been definitively established for clinical use in PSC. Clinical, endoscopic, radiological and histological examinations are required to establish a diagnosis of IBD. PSC associated IBD is phenotypically and genetically distinct from IBD in the absence of PSC. PSC patients are subject to a number of significant events throughout fluctuating and highly variable course. Treatment recommendations in terms of liver disease modifying therapies or dominant strictures management are limited by the lack of robust data. Given the unmet need for effective medical treatments for PSC to

date, most patients ultimately require liver transplantation.

DEMOGRAPHIC AND PROGNOSTIC DATA IN A CROATIAN COHORT OF PATIENTS WITH PRIMARY BILIARY CHOLANGITIS

Tonci Bozin1, Anita Madir2, Marko Lucijanic3, Ivica Grgurevic1

1University Hospital Dubrava, Department of Gastroenterology, Hepatology and Clinical Nutrition, Zagreb, Croatia; 2Zagreb University School of Medicine, Zagreb, Croatia; 3University Hospital Dubrava, Department of Haematology, Zagreb, Croatia

BACKGROUND AND AIM: The aim of this investigation was to present demographic characteristics of a cohort of PBC patients, as well as to identify prognostic factors for adverse outcomes.

PATIENTS AND METHODS: We conducted a retrospective analysis of a cohort of PBC patients followed in University Hospital Dubrava. We identified 74 patients of whom 51 were included in the present study. Patients with overlap syndromes and HBV or HCV infection were excluded. Patients were categorized as having early or late-stage disease. Early stage was defined as histologic grade I or II, and/or normal bilirubin and albumin values at enrolment. Response to UDCA therapy was evaluated accordingly, in a 12 month

period. We used Paris IIb criteria for early stage disease and Paris I criteria for late-stage disease. Composite endpoints were defined as presence of ascites, variceal bleeding, hepatic encephalopathy, HCC, death or transplantation.

RESULTS: Median age at diagnosis was 54 with 84.3% of patients being female. Liver biopsy was performed in 38 (74,5%) patients. The most prevailing symptom was nausea in 27/51 (52.9%) and pruritus was observed in 11/51 (21.6%) of patients. Osteoporosis was recorded in 8/51 (15.7%) patients, and a second autoimmune disease in 22/51 (43.1%) patients. Three patients were not taking UDCA. Response to UDCA was observed in 71.7% of patients. 27/51 (52.9%) of patients were early-stage. AST >2.5 UNL, albumin <40 g/L, PT <70% were univariately significantly associated with not responding to UDCA therapy. In multivariate logistic regression analysis, albumin <40g/L remained only variable significantly associated with poor response to UDCA therapy, OR 8.23 95% C.I [1.17 - 57.92].

Median follow up of our cohort was 6 years. Median time to composite event was not reached. Event free rate at 5 years was 85.5%. Factors that were univariately associated with experiencing an event were non-response to therapy (P=0.001), advanced disease stage (P=0.006), osteoporosis (P=0.047), AST >2.5 UNL (P=0.002), ALP >2.5 UNL (P=0.046), albumin <40 g/L (P=0.014) and PT <70% (P=0.010). In multivariate Cox regression analysis non-response to therapy remained only factor independently associated with higher risk of experiencing adverse event (HR 7.06, P=0.042).

CONCLUSION: Among multiple factors associated with disease severity, only low albumin remained independently predictive of therapy failure. Non-response to therapy was only parameter independently prognostic of composite adverse event in patients with PBC.

CLINICAL FEATURES OF PRIMARY BILIARY CHOLANGITIS – REAL LIFE DATA FROM SLOVENIA

Katja Novak

Department of Gastroenterology, University Medical Center Ljubljana, Slovenia; E-mail: [email protected]

In Clinical department of Gastroenterology in University Medical Center Ljubljana we have a database of patients with PBC treated from 1984 to 2010. Their medical records were reviewed and database was updated to the end of 2017. Diagnosis of PBC was made by clinical criteria which were compliant with recent recommendations of European Associa-tion for the Study of the Liver (EASL). Apart from demographic features of patients, we examined the outcome of the disease, occurrence of symptoms and signs of cirrhosis, as well as associated diseases, such as autoimmune diseases.

In our group of 174 patients, which are predominantly females, the average age at the time of diagnosis is 53. The average observation time is 11,5 years. 89% of patients were treated with ursodeoxycholic acid in recommended doses. We calculated GLOBE score in those

patients with available data and our results showed that the transplant-free survival is diminished in 20,9% of patients.

In 31,6% of patients signs of liver cirrhosis developed in average in 9,46 years. 9,7% of patients were treated with liver transplantation on average in 9,2 years from diagnosis. In our group 28,1% of patients died until end of 2017. Despite unfavorable diagnosis of chronic liver disease survival rates in our group of PBC patients are excellent: one-year survival from time of diagno-sis is 99,4% and ten-years survival is 89,9%, respectively.

INFECTIVE CAUSES OF CHOLESTASISKrzysztof Tomasiewicz, Prof, MD PhD

Department of Infectious Diseases and Hepatology, Medical University of Lublin, Poland;

E-mail: [email protected]

There are many extrahepatic infections that may cause cholestasis. They include viral, bacterial and fungal diseases. The role in pathophysiology of infectious agent in cholestatic liver disease may be the direct effect within the liver or biliary system and/or immune-mediated reaction.

It is well documented in analysis of sepsis accompanied cholestasis it can be caused both by Gram-negative and Gram-positive bacteria, however with predominance of E. coli. Kupffer cells, hepatocytes and sinusoidal endothelial cells react to bacterial endotoxins with increased secretion of proinflammatory cytokines. Hepatocellular and canalicular bilirubinostasis and nonspecific portal-based inflammation and Kupffer cell hyperplasia may be seen. Progressive sclerosing cholangitis can emerge in the setting of severe septic shock and may lead to liver cirrhosis. Actinomycosis, shigellosis, brucellosis and yersiniosis are bacterial diseases with possible cholestatic signs and symptoms.

Both Mycobacterium tuberculosis and M. avium complex may present with dramatic cholesta-sis. In differential diagnosis of jaundice in these cases the potential risk of extrahepatic biliary obstruction should be considered, as mycobacterial infection may cause intra-abdominal lymphadenopathy.

Hepatic involvement in systemic mycoses is infrequent. In rare cases disseminated fungal infection may lead to varying degrees of cholestasis. Cholangitis can be present in Cryptococ-cus neoformans infection and hepatic candidiasis may include inflammation and edema surrounding bile ducts as well as suppurative granulomas.

Most of hepatotropic viruses may cause cholestatic form of hepatitis. Otherwise noncompli-cated course of acute hepatitis A may become problematic as progressively increasing choles-tatic jaundice and intense pruritis can be present. Moreover HCV infection is associated with

higher incidence of possibly severe intrahepatic cholestasis of pregnancy (ICP). CMV infection may have specific cholestatic features in immunocompromised patients.

With huge number of infective causes of cholestatic liver diseases the proper and prompt diagnosis is a basis for appropriate management. Underlying conditions and causes, including drugs and herbs should be included in differential diagnosis of cholestasis.

NUTRITIONAL STATUS IN CHOLESTATIC LIVER DISEASES

Zeljko Krznaric, Prof, MD PhD, FEBGH

Clinical Hospital Centre Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia

Nutrition has long been recognized as a prognostic factor in patients with chronic liver disease including cholestatic livers diseases like PBC and PSC. Unfortunately even today, not all physicians consider nutrition issues in the management of their liver patients. It is important to present an evidence base for nutritional management of patients with choles-tatic liver diseases according actual scientific and clinical data. Update of EASL and ESPEN guidelines are needed to include new data on nutrition including the role of microbiota.

The assessment of nutritional risk of patients must include the nutritional status and the course of the disease as well our actions like different medical or surgical interventions. Clinical assessment of nutritional status should include not only body weight and height as well as BMI but also information on energy and nutrient balance and body composition. History of the disease about nutritional intake, involuntary weight loss or weight gain during the time period is relevant. NRS-2002 and MUST are validated tools to screen hospitalized patients for risk of malnutrition and are recommended by ESPEN.

Several studies have shown higher rates of mortality and complications, such as refractory ascites, variceal bleeding, infection, and hepatic encephalopathy in cirrhotic patients with PEM as well as reduced survival.

Some studies have shown higher morbidity and mortality in liver cirrhosis patients with protein malnutrition when such patients undergo surgery or liver transplantation. Sarcope-nia and frailty brings increased risk of morbidity and mortality for patients on the waiting list for transplantation and after liver transplantation.

In general, deficiency in fat soluble vitamins has been observed in cholestasis-related steator-rhoea and bile salt deficiency. Dietary modifications, ONS, enteral nutrition and parenteral nutrition are part of the nutritional management of liver disease patients according clinical stage and ESPEN guidelines.

References

1. Plauth, M. et al. ESPEN Guidelines on Enteral Nutrition: Liver disease. Clinical Nutrition , Volume 25 (2006.) , Issue 2 ,

285 – 294.

2. Plauth, Mathias et al. ESPEN Guidelines on Parenteral Nutrition: Hepatology. Clinical Nutrition , Volume 28 (2009.) , Issue 4 , 436 - 444

3. Cederholm, T. et al. Diagnostic criteria for malnutrition – An ESPEN Consensus Statement. Clinical Nutrition , Volume 34 (2015.) , Issue 3 , 335 - 340

PRURITUS AND OTHER COMPLICATIONS OF CHOLESTASISLucija Virović Jukić, MD PhD, Asst Prof.

University of Zagreb School of Medicine, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia

Cholestasis is associated with many hepatobiliary disorders that produce extrahepatic biliary obstruction or intrahepatic biliary stasis, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy (ICP), benign or malignant biliary obstruction, drug-induced cholestasis (DILI), chronic hepatitis or cirrhosis, and inherited cholestasis syndromes.

Pruritus is one of the most troublesome symptoms and can develop in cholestasis due to any cause. It is most commonly seen in patients with ICP, PBC and malignant biliary tract obstruc-tions, and less commonly in other cholestatic conditions. The pathogenesis is unknown, but several hypotheses try to explain its development. Elevated levels of bile acid in the skin may act as pruritogens directly, or by altering hepatocyte membranes and enabling release of pruritogenic hepatic contents into the bloodstream. Other theories imply the roles of endogenous opioids and lysophosphatidic acid, a phospholipid formed by the action of autotaxin. These substances therefore represent potential therapeutic targets for the treatment of pruritus.

The management of the cholestasis-associated pruritus requires the management of the underlying disease by pharmacologic measures (e.g. ursodeoxycholic acid), endoscopic treatment of strictures, discontinuation of the medication in DILI, etc. Symptomatic measures include antihistamines and emollients in mild cases, and bile acid sequestrants (cholestyramine) and rifampin in more severe cases. Alternative options for cases refractory to standard treatment include opioid antagonists such as naltrexone, phenobarbital, sertraline and gabapentin. Experimental treatments include novel ileal bile acid transport inhibitors, phototherapy, plasmapheresis and nasobiliary drainage. If medical treatment fails, liver transplantation may be the only effective therapeutic option.

Other common complications of cholestasis include: diarrhea and weight loss due to malabsorption of dietary fat, deficiencies of fat-soluble vitamins (A, D, E and K) with related symptoms and metabolic bone disease. Treatment of the underlying disease process is the first therapeutic strategy, followed by symptomatic measures (restriction of dietary fat, supplementation of medium-chain triglycerides and vitamins), with liver transplantation

being the final option.

References:

European Association for the Study of the Liver: EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol 2009;51:237-267.

European Association for the Study of the Liver: EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017;67:145-172.

CHOLESTATIC LIVER DISEASE DURING THE PREGNANCY

Ivana Mikolasevic, Asst. Prof, MD, PhD

Department of Gastroenterology, University Hospital Centre Rijeka, Croatia;

Email: [email protected]

One of the least studied topics in the field of obstetrics is liver disease during pregnancy, which creates a challenge for both gynecologists and hepatologists. Approximately 3% of pregnant women are affected by some form of liver disease during pregnancy. Three types of liver disease need to be differentiated during pregnancy. One type is liver disease directly related to pregnancy, which can occur at a specific time during pregnancy. Another type is liver disease not related to pregnancy, which can occur at any time, such as viral or drug-induced hepatitis. Furthermore, pregnancy can occur in women with pre-existing liver disease. Intrahepatic cholestasis of pregnancy (ICP) is the most common cause of cholestasis during pregnancy and the most common pregnancy-related liver disease. ICP is a form of liver disease characterized by a reversible cholestatic condition that usually occurs during the late second and third trimester, though rarely it can be present as early as 7 weeks of gestation. ICP has rapid postnatal resolution, with signs and symptoms usually disappearing spontaneously within 6 weeks of delivery. ICP recurs in more than half of subsequent pregnancies. The main symptom of ICP is pruritus, which typically predominates on the palms and soles of the feet and worsens at night. Pruritus often develops after 25 weeks of gestation, with 80% of cases occurring after the 30th week. Other symptoms of ICP can include steatorrhea, malabsorption of fat-soluble vitamins, and weight loss due to cholesta-sis. The goals of ICP treatment are to reduce maternal symptoms, improve laboratory tests and improve fetal outcome. The first therapy for ICP is ursodeoxycholic acid (UDCA) at a dose of 500 mg twice a day or 15 mg/kg per day. UDCA is safe in the third trimester because no maternal or fetal adverse effects have been reported regarding the use of this medication in ICP.

References:

Mikolasevic I, Filipec-Kanizaj T, Jakopcic I, et al. A challenging clinical issue: liver disease during pregnancy. Med Sci Monitor, 2018.

Westbrook RH, Dusheiko G, Williamson C. Pregnancy and liver disease. J Hepatol 2016;64:933-45.

Kamimura K, Abe H, Kawai H, et al. Advances in understanding and treating liver diseases during pregnancy: A review. World J Gastroenterol 2015;21:5183-90.

QUALITY OF LIFE IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS

Tamara Milovanovic Alempijevic, Assoc Prof, MD PhD

Faculty of Medicine, University of Belgrade, Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Belgrade, Serbia; E-mail: [email protected]

Primary biliary cholangitis (PBC) is a chronic, potentially life-threatening, autoimmune choles-tatic liver disease exemplified by the presence of autoantibodies: anti-mitochondrial antibod-ies (AMA), and specific anti-nuclear antibody (ANA) subtypes. In keeping with its autoim-mune origin, PBC primarily effects women and is associated with a significantly higher symptom burden than other chronic liver diseases (CLD), consequently negatively impacting patient's HRQOL. Progressing slowly, the most common symptoms are dilapidating fatigue, itch and cognitive impairment which may occur at any point, independent of the histological stage of the disease. Initial investigations assessing cholestatic liver diseases and health-related quality of life (HRQOL) found, that compared to other CLD patients, those with PBC had significantly lower quality of life scores. Further studies investigating the HRQOL of patients with PBC, demonstrated an urgent need for a disease specific instrument, separate from other CLD and general quality of life questionnaires including the chronic liver disease questionnaire (CLDQ) and the short form health survey-36. To meet this necessity, Jacoby et al, created the first disease specific quality of life scale for PBC, the PBC-40, which was evaluated and found to have appropriate validity and reliability alongside the creation of the shorter PBC-27. The aim of herein presentation will be assessment of quality of life in patients with primary biliary cholangitis.

HISTOLOGY OF CHOLESTATIC LIVER DISEASES

Anita Skrtic, MD PhD, Asst Prof.1,2

1Department of Pathology, University Hospital Merkur, Zagreb; 2Department of Pathology, School of Medicine University of Zagreb, Zagreb

Modern imaging methods have reduced the need for liver biopsy in jaundiced patients. Nevertheless, biopsy is still helpful in some instances when the cause of a presumed intrahe-patic jaundice is in doubt, when there is a need to distinguish between acute and chronic liver disease, and when other investigations give equivocal results.

Cholestasis is an important finding in large bile-duct obstruction or in extensive intrahepatic bile-duct disease, but may also accompany the parenchymal damage in certain types of hepatitis. Morphologically, it is presented with visible bile in liver tissue sections.

In a broad spectrum of liver diseases two main types of cholestasis could be observed in liver tissue, canalicular and ductular form of cholestasis regarding the aetiology of cholestatic liver injury.

Pure cholestasis as an isolated lesion requires consideration of several possible aetiologies which may not be distinguishable by light microscopy alone.

The diagnostic algorithm of liver dysfunction following liver, kidney or haematopoietic cell transplantation is also reliant on information from liver biopsies, which must be reported promptly and with due consideration that the pathological changes in these patients may reflect more than one aetiological factor.

Liver biopsy is one of diagnostic tools used in the evaluation and management of patients with cholestatic liver disease which continuous to play an important role because the concepts and classifications of liver disease are rooted in morphology.

The pathologist’s report can answer important clinical questions such as disease causation and activity, and is important in therapeutic decision-making which has substantial impact on

patient care. References:

2. Jay H. Lefkowitch. Scheuer’s Liver Biopsy Interpretation. Churchill Livingstone 9th edition © ۲۰۱٦, Elsevier Limited.

MRI IN CHOLESTATIC LIVER DISEASES

Renata Huzjan Korunic, Asst Prof, MD PhD

Department of Diagnostic and Interventional Radiology, University Hospital Dubrava, University of Zagreb School of Medicine, Zagreb, Croatia; E-mail: [email protected]

Cholestatic liver diseases are result of disruption of bile flow on intrahepatic level or as a result of extrahepatic bile ducts obstruction. Magnetic Resonance Imaging (MRI) with MRCP is a non-invasive and non-ionizing imaging modality and as such it has become the standard method for morphological examination of the bile ducts. It enables detection of duct morphology, anatomy, areas of stenosis and dilatation, presence of stones within the ducts, as well as liver parenchyma diffuse changes and focal lesions. On many instances it can replace the more invasive techniques and even the liver biopsy. Primary Sclerosing Cholangi-tis (PSC) and Primary Biliary Cirrhosis (PBC) are the most common immune-mediated chronic cholestatic liver diseases leading to cirrhosis and liver failure. In PSC MRI with MRCP is a reference procedure with typical findings in many cases. MRI is also valuable method for follow up of the selected groups of patients in regard of monitoring the disease progression and timely diagnosis of possible malignant transformation. The most important extrahepatic reasons of bile duct obstruction including stones, strictures and malignant tumours are also discussed. The limitations of technique are explained.

Refrences

Kovač et al. Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis: an Update on MR Imaging Findings with Recent

Developments. J Gastrointestin Liver Dis 2016;25(4):517-24

Arrive L. Et al. MRI of cholangitis: Traps and Tips. Diagnostic and Interventional Imaging 2013;94:757-70

Mohammad Alizadeh AH. Cholangitis: Diagnosis, Treatment and Prognosis. J Clin Transl Hepatol 2017;5(4):404-13

ENDOSCOPIC ULTRASOUND IN CHOLESTATIC DISEASE

Mario Tadic, MD PhD, Asst Prof

Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, Zagreb, Croatia

Endoscopic ultrasound (EUS) is method that is being increasingly used for assessment of pancreatobiliary tract diseases (PBTD). Accuracy and safety has made this method very attractive for evaluation of PBTD. EUS with significantly lower complication rate comparing to endoscopic retrograde cholangiopancreatography (ERCP) has completely rule out the later from diagnostic use in PTBD. The role of endoscopic ultrasound is generally well assessed in detection and characterization of pancreatic diseases. In evaluation of cholestatic disease EUS has strong competitors in transabdominal ultrasound, computed tomography, magnetic resonance and ERCP. The first three methods have significantly increased accuracy in evalua-tion of PTBD due to technological advances in last years. These methods are noninvasive and are able to evaluate both intrahepatic and extrahepatic cholestatic pathology with same accuracy. On the other hand EUS is in general limited to extrahepatic cholestatic pathology. However, EUS offers more than pure imaging. EUS offers the possibility of tissue sampling. EUS guided tissue sampling enables characterization of detected PTBD and, in some cases, is able to replace or rule out ERCP based sampling methods. Recently, EUS has gone beyond diagnostic method and become used as platform for biliary therapeutic interventions. While the EUS guided interventions seems very appealing, their place is yet to be determined.

ELASTOGRAPHY IN CHOLESTATIC LIVER DISEASES

Emmanuel Tsochatzis MD, MSc, FEBTM, PhD, Senior Clinical Lecturer and Honorary Consultant in Hepatology

UCL Institute for Liver and Digestive Health, Royal Free Hospital Pond Street NW3 2QG London; Academic email: [email protected]; NHS email: [email protected]

The emergence of non-invasive tests (NITs) for the assessment of liver fibrosis has revolution-ised clinical hepatology. NITs have progressed at a rapid rate from development to acceptance at the bedside and in consensus guidelines. Elastography is one of the most validated non-invasive techniques and has the advantage of directly measuring liver stiffness, which correlates with fibrosis and portal hypertension. I will present data on the evaluation of liver fibrosis in PBC and PSC using elastography techniques. I will also present data on the assessment of portal hypertension, including the Baveno criteria for sparing screening endoscopies for varices assessment in patients with compensated advanced chronic liver

disease.

SEROLOGICAL TESTS IN CHOLESTATIC LIVER DISEASES

Nermin Salkić, Prof, MD PhD

University Clinical Center Tuzla, Deptartment of Gastroenterology and Hepatolog, Tuzla, Bosnia and Herzegovina

Fibrosis assessment is an important step in the prognosis and evaluation of cholestatic liver diseases (PBC and PSC). Despite the fact that liver biopsy is still considered as gold standard for these diseases, it is an imperfect gold standard, and physicians now have several clinically tested and validated noninvasive methods to evaluate presence and degree of fibrosis, as well as to evaluate prognosis in both PBC and PSC. In PBC, transient elastography (TE) remains as the noninvasive method with best accuracy, however several serological tests, such as APRI score, ELF, FIB-4 and hyaluronic acid level emerge as fast and applicable methods with nearly comparable diagnostic accuracy. APRI score and hyaluronic acid level are also well evaluated in terms of their prognostic value in PBC which is confirmed in several reports. In PSC, serological tests are not sufficiently validated in contrast with TE, yet hyaluronic acid levels and APRI seem promising. Prognostic value of ELF score in PSC is validated and is comparable to TE, as they allow stratification of patients into low-, intermedi-ate-, and high-risk groups for liver-related death, liver complications, or liver transplantation.

BIOMARKERS OF BILIARY-GUT CROSS-TALK IN CHOLESTASIS

Maria Papp, MD PhD

University of Debrecen, Faculty of Medicine, Department of Internal Medicine, Division of Gastroenterology

Clinical manifestations and progression of primary sclerosing cholangitis (PSC) are heteroge-neous, while the pathogenesis of the disease is poorly understood. A large body of clinical evidence has certified importance of gut-liver interaction in the pathogenesis of the disease. One of the mechanistic theories highlights the importance of gut-liver axis. Recent advances in the filed of biomarkers of biliary-gut cross-talk may mark clinically relevant pathogenic subgroups in the disease spectrum of PSC assisting everyday clinical work-up (e.g. diagnosis, disease stratification or surveillance) and also the exploration of potential therapeutic targets. Currently, these are significant unmet needs in this patient population.

Alkaline phosphatase (ALP) produced by biliary epithelium of the liver. It is consistently associated with prognosis across studies and a component of several clinical risk scores. However, the naturally fluctuating course of ALP in PSC complicates its use in individual patients. Elevated IgG4 is associated with a shorter OLTx-free survival. IgG type perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) is a non-specific marker of various autoim-mune liver diseases and may reflect B-cell response to antigens of gut origin. P-ANCA

directed against cytoskeletal human β-tubulin isotype 5 (TBB-5) cross-reacting with the bacterial protein FtsZ, probably reflecting an abnormal immune response to intestinal microorganisms in susceptible, genetically predisposed individuals. IgG P-ANCA identify PSC patients with particular clinical and HLA genetic characteristics but not correlate with need for OLTx, development of CC or death. Biliary IgG P-ANCA or calprotectin are highly sugges-tive for PSC and correlates with the severity of bile duct strictures and the ensuing biliary complications. Biliary markers however require invasive procedure for sampling, reducing utility in clinical follow-up. Inflammatory marker, IL-8 predicted clinical outcome in PSC. IgA type F-actin antibody (AAA) identified PSC patients with progressive disease course and associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage. In autoimmune hepatitis AAA seropositivity was associated to HLA-DR3 positivity. Cytoskeletal F-actin is a novel extracellular damage-associated molecular pattern (DAMP) signal coupled by dendritic receptor DNGR-1/CLEC9A. Syk-SFK signalling results in antigen cross-presentation to CD8+T-cells. CD8+T-cells being activated in gut are able to be recruited to liver via enterohepatic circuit and were found to induce immune-mediated cholangitis in mice. IgA type anti-glycoprotein 2 (GP2) antibody has just been identified as a novel marker of PSC amongst different chronic liver diseases. IgA anti-GP2 also identified a subgroup of patients with severe phenotype and poor survival due to enhanced fibrogenesis or development of CC. Anti-GP2 represents loss of tolerance to gut immunity protein. Glycoprotein 2 can interact with FimH-positive bacteria. GP2-mediated transcytosis is necessary for the initiation of antigen-specific mucosal immune responses against this type of bacterial antigen. FimH is also a novel ligand of toll-like receptor 4. Sustained TLR4 activation leads to enhanced fibrosis through TGF-beta signalling.

PREDICTIVE FACTORS FOR THE EFFECTIVENESS OF PRIMARY BILIARY CHOLANGITIS TREAT-MENT WITH URSODIOL1Drazilova S, 2Gazda J, 2Janicko M, 1Martinkova D, 1Mikolajova L, 2Jarcuska P. 1Dept of Internal Medicine, Hospital Poprad, Slovakia; 21st Dept of Internal Medicine, University of PJ Safarik, Faculty of Medicine and University Hospital L. Pasteur, Kosice, Slovakia

Background: Ursodeoxycholic acid (UDCA) is the gold standard in the therapy of primary biliary cholangitis (PBC), but some patients despite of this treatment can progress to liver cirrhosis and hepatocellular cancer. Aim of the study was to find predictive factors for the therapeutic response to the Ursodiol treatment at month 6 and 12.

Patients: We performed retrospective analysis of 89 patients with PBC (88 female, mean age: 55±10.1 years) treated by Ursodiol. Treatment response to the Ursodiol treatment was defined by ALP level < 1,67 ULN and bilirubine level < 2 ULN at month 6 or 12 of UDCA therapy.

Results: Baseline conjugated bilirubin (p=0.004), AST (p=0.004), ALT (p=0.005) and ALP

(p=0.001) were predictive factors of the therapeutic response to UDCA treatment at month 6, while baseline total bilirubine (p=0.003), conjugated bilirubine (p=0.002) and ALP (p=0.017) predicted a therapeutic response to UDCA at month 12.

Therapeutic response to UDCA at month 6 was a strong predictive factor to achieve a therapeutic response at month 12 of Ursodiol treatment (OR 12.75, 95%CI 4.01-40.50; p<0,001).

Patients with baseline ALP ≤ 2 ULN had a significantly greater chance for achievement of the therapeutic response at month 6 of UDCA therapy (p<0.001), but not at month 12 of therapy compared to patients with baseline ALP > 2 ULN.

Patients who didn´t achieve a therapeutic response to the UDCA at month 6 or 12 had a significantly higher chance to develop decompensation of liver disease in the future (at month 6: OR 9.7391, 95%CI 1.9201-49.3985; p=0.003; at month 12: OR 11.5938, 95%CI 2.1869 -61.4641; p=0,002)

Conclusion: Baseline laboratory parameters have variable statistical power for prediction of the treatment response to Ursodiol therapy at month 6 and 12. Response to Ursodiol at month 6 is a strong predictor of Ursodiol response at month 12. Non-response to UDCA treatment predicts decompensation of advanced liver disease in the future.

NOVEL TREATMENT OPTIONS FOR CHOLESTATIC LIVER DISEASESIvica Grgurevic, Assoc Prof, MD PhD, FEBGH

Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, Department of Internal Medicine, University of Zagreb School of Medicine and Faculty of Pharmacy and Biochemistry, Zagreb, CROATIA; E-mail: [email protected]

Ursodesoxycholic acid (UDCA), current standard of care (SOC) for primary biliary cholangitis (PBC) is ineffective in arround 40% of patients according to biochemically defined response criteria (serum alkaline phosphatase (ALP) and biliurubin), and in general does not improve outcomes in patients with primary sclerosing cholangitis (PSC). Novel agents have been recently introduced, and some are still being evaluated in clinical trials. Currently the most promissing agent for PBC is obeticholic acid (OCA), steroidal agonist of nuclear Farnesoid X receptors (FXR) that has been demonstrated to effectively decrease levels of ALP and bilirubin in PBC patients unresponsive or intolerant to UDCA. OCA has been evaluated in Phase 3 clinical trial lasting for 24 months, and the most important adverse effect was pruritus for which the treatment had to be discontinued in 4% of patients. Prospective trial to address long-term effects and outcomes OCA treated PBC patients is underway (COBALT trial, NCT02308111). NGM-282 is a nonsteroidal (recombinant protein identical to FGF-19) FXR agonist. In phase 2 study (NCT02135536) NGM282 applied 0.3 or 3mg vs placebo (PBO) as a daily SC injection for 28 days resulted in significant reduction in ALP (-15,8%, -19,2% and -1,2% from baseline, respectively) in PBC patients. Peroxisome proliferator-activated

receptor alpha agonists (fibrates) have been also investigated for their ability to reduce transcription of inflammatory genes, reduce bile acids’ syntesis and increase phospholipid biliary content. Fenofibrate in addition to UDCA was demonstrated to significantly reduce ALP as compared to UDCA alone in PBC patients. The same effect was observed in BEZURSO trial using bezafibrate in UDCA unresponsive PBC patients. Nor-UDCA conjugation-resistant, and more hydrophilic homologue of UDCA is passively absorbed by cholangiocytes, undergoes cholehepatic shunting, which allows ductular targeting and promotes biliary bicarbonate secretion that renders bile duct epithelial cells more resistant toward toxic bile. In phase II clinical trial norUDCA reduced serum ALP levels in PSC patients within 12 weeks in dose-dependent manner, whereas safety profile of norUDCA was excellent. Results of OCA in PSC patients have been recently reported in AESOP trial (NCT02177136): Least Squares mean percent change of ALP from baseline at week 24 was significantly higher for OCA as compared to placebo (-22% vs +1%; p<0,05). Investigational agents for PSC/PBC include Vascular adhesion protein-1 human monoclonal antibody, Cenicriviroc, CCR5 and CCR2 antagonist, Simtuzumab (GS-6624) Lysyl oxidase homolog 2 (LOXL2) monoclonal antibody, FGF-19 analog NGM282, ASBT inhibitor LUM001.

References:

Nevens F. N Engl J Med 2016;375:631-43.

Ali AH, Lindor KD. Clin Liv Dis 2016; 8(5): 132-135

Khanna A. Ther Adv Gastroenterol 2017, Vol. 10(10) 791–803

Cheung AC. Aliment Pharmacol Ther 2016; 43: 283–293

Fickert P. J. Hepatol. 2017, 67, 549–558

PHARMACOLOGICAL INTERVENTIONS FOR PSC AND PBC: AN ATTEMPTED NETWORK META-ANALYSIS

Francesca Saffioti, MD

Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, University College London & Royal Free London NHS Foundation Trust, London, United Kingdom; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic choles-tatic liver diseases, which commonly progress to liver cirrhosis and its complications. The optimal pharmaceutical treatment of both diseases remains controversial, and various pharmacological agents have been evaluated. Ursodeoxycholic acid (UDCA) is the standard of care for PBC, however one Cochrane Review reported no survival or symptomatic benefit for UDCA compared to placebo or no intervention. Nevertheless, it is generally accepted that a majority of UDCA-treated PBC individuals exhibit a treatment response, while 30% of patients do not meet response criteria, presenting a more progressive disease phenotype. Obeticholic acid has recently been approved for the treatment of PBC, but its long-term effects are still unknown. Therefore, liver transplantation remains the only curative

treatment for PSC and for advanced end-stage PBC.

We performed two systematic reviews to assess the comparative benefits and harms of different pharmacological interventions for patients with PSC and PBC. Only randomized controlled trials (RCTs) of various pharmacological interventions compared with each other or with placebo were included. We also planned to conduct a network meta-analysis that would allow comparison of many different individual treatments as reported by research trials. However, because of the nature of the available information, we could not determine whether results of the network meta-analyses were reliable. Therefore, standard Cochrane methods were used.

The overall quality of evidence was very low and all the trials were at high risk of bias, increas-ing the possibility of making wrong conclusions overestimating benefits or underestimating harms of one treatment or the other.

Evidence is currently insufficient to show differences in effectiveness measures such as mortality, health-related quality of life, cirrhosis, or liver transplantation between any active pharmacological intervention and no intervention.

An urgent need exists to identify effective medical treatments for PSC and PBC, through well-designed RCTs with adequate follow-up.

References:

Karlsen TH. J Hepatol. 2017 Dec;1323-1298:(6)67.

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017; 67(1):145-172.

Saffioti F. Cochrane Database of Systematic Reviews 2017, Issue 3. Art. No.: CD011343.

ENDOSCOPIC MANAGEMENT OF BILIARY STRICTURES

Tomislav Bokun, MD PhD

Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, Zagreb, Croatia; Email: [email protected]

Cholangiopathies are chronic progressive liver diseases that arise from and/or involve cholangiocytes as the central target cell. They can be classi�ed into following broad groups: idiopathic, malignant, genetic, and secondary sclerosing cholangitis. The most common cholangiopathy that presents with benign biliary strictures is primary sclerosing cholangitis (PSC), often progressive disease leading to end-stage liver disease. The main concern in the management of benign biliary strictures in general is to be sure the stricture is benign i.e not to miss malignant biliary strictures, which are substantially more common in patients PSC compared to general population. However, in real life practice di�erential diagnosis of benign vs. malignant biliary strictures is often quite challenging. Dominant

biliary strictures in symptomatic PSC patients should be treated endoscopically. Pruritus and pain are likely to improve and bilirubin level decrease after endoscopic treatment of dominant stricture(s), and cholangitis is less likely to recur. However, in patients with end-stage liver disease endoscopic treatment provides small or no bene�t and these patients should be considered of liver transplantation. Ductal sampling by brush cytology and/or endobiliary biopsies should be considered at the occasion of endoscopic treatment. Upon brushing, cytological analysis should be undertaken, as well as �uores-cence in situ hybridization if cytology �ndings are not clear. Data so far suggests that balloon dilation alone might be a better treatment option due to less adverse events, but the severity and length of the stricture, presence of cholangitis, as well as endoscopist’s experience and preference should be considered. Dilation diameter should be in line with the diameter of adjacent normal duct, and the need for repeated dilation of relapsing dominant strictures is common. If biliary stenting is the method of treatment, short term stent placement is suggested, up to two weeks. Many endoscopists prefer to perform small endoscopic sphincterotomy, and antibiotics should be routinely administered before the endoscopic treatment. Clinical re-evaluation including MRCP and ERCP with brushing or endobiliary biopsies is indicated in patients with established diagnosis of PSC and rapid worsening of cholestasis and pruritus, cholangitis, weight loss, raise in tumour marker Ca 19-9, progression of dilation of biliary tree on cross sectional imaging, as well as with progression of known and formation of new strictures.

References

Lazaridis KN, LaRusso NF. Primary Sclerosing Cholangitis. N Engl J Med. 2016;375:1161–1170.

Aabakken L, Karlsen T, Albert J, et al. Role of endoscopy in primary sclerosing cholangitis: European Society of Gastroin-testinal Endoscopy (ESGE) and European Association for the Study of the Liver (EASL) Clinical Guideline. Endoscopy. 2017;49:588–608.

Hu B, Sun B, Cai Q, et al. Asia-Pacific consensus guidelines for endoscopic management of benign biliary strictures. Gastrointest Endosc. 2017;86:44–58.

LIVER TRANSPLANTATION IN CHOLESTATIC LIVER DISEASESTajana Filipec Kanizaj, Assoc Prof, MD PhD

Department of Gastroenterology, University hospital Merkur, School of Medicine, University of Zagreb., Zagreb, Croatia

Liver transplantation (LT) is the treatment of choice for patients with advanced liver disease due to various cholestatic liver diseases.i Outcomes for LT in these indications are comparable to transplants for other indications (5-year survival rates > 80-85%).ii,iii

Primary sclerosing cholangitis (PSC)

Most of the indications for LT in PSC patients are similar to those in other forms of end-stage liver disease.iv MELD score has become the primary tool for predicting prognosis in patients with PSC and to allocate prioritization for LT. Patients should generally be referred for LT once

their MELD score ≥ 15. There are special circumstances in which LT may be indicated despite a low MELD score. These may include: recurrent or refractory cholangitis and or biliary sepsis, intractable pruritus, cholangiocarcinoma <3 cm in diameter (in the context of a clinical trial). Evaluation of PSC patients for LT is inherently difficult due to the unpredictability of the disease course and the high risk of biliary tract malignancy.

Ten-year incidence of recurrent PSC following LT is 14-20%.v Risk factors for recurrence remain incompletely understood, with possibility that colectomy before and during initial LT for PSC is protective against recurrence.vi Only approximately 1/3 of patients with recurrence develop progressive disease leading to retransplantation or death.

Primary biliary cholangitis (PBC)

PBC is a common, albeit decreasing, indication for LT. LT should be strongly considered if complications of cirrhosis have occurred (MELD score ≥ 15), progressively rising bilirubin level (>85 µmol/L), or intractable pruritus with an unacceptable quality of life. Ten-years disease recurrence rate after LT is up to 30%, but the rate of histological recurrence is likely higher. Among factors proposed to affect the rate of recurrence is the use of tacrolimus. Treatment with UDCA lowers liver enzymes and may lower the incidence of recurrent PBC, but there is insufficient evidence to make an absolute recommendation for its use post-transplant.vii Current evidence does not suggest an impact of recurrent PSC on graft or patient survivali European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Liver transplantation. J Hepatol 2015ii Dickson ER, Murtaugh PA, Wiesner RH, et al. Primary sclerosing cholangitis: refinement and validation of survival models. Gastroenterology. 1992;103(6):1893. iii European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237.iv Lindor KD, Kowdley KV, Harrison ME, et al. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol. 2015;110(5):646. v Ravikumar R, Tsochatzis E, Jose S, et al. Risk factors for recurrent primary sclerosing cholangitis after liver transplantation.J Hepatol. 2015 Nov;63(5):1139.vi Alabraba E, Nightingale P, Gunson B, et al. A reevaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts. Liver Transpl. 2009;15(3):330. vii European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017;67:145.

EPIDEMIOLOGY OF CHOLESTATIC LIVER DISEASES (ChLD)

Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Katja Novak

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285 – 294.

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Maria Papp, MD PhD

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informationVENUE

Main Lecture Hall University Hospital Dubrava

Av. Gojka Suska 6, Zagreb 10 000, Croatia

500 HRK for physiciansstudents, residents and nurses: free

The registration fee covers course participation withUS Hands-on, syllabus, co�ee breaks, lunch and dinner.

All delegates will receive a certificate of attendance.

For information about registration, hotel accommodationand travel details contact: Jasenka DuvnjakCroatian Society of Gastroenterology O�ce

Marticeva 72, 10 000 ZagrebEmail: [email protected]

Phone: 00385 1 2442 398; 00385 1 4651 214Fax: 00385 1 4621 958

Mobile: 00385 99 462 1958

REGISTRATION FEE

Katja Novak

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285 – 294.

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disease.

Maria Papp, MD PhD

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Adriatic Liver Forum: CHOLESTATIC · CHOLESTATIC ˜˚˛˝˙ˆˇˆ˙˛ ˘˜ ˆ ˝˘ President of...

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Transcript of Adriatic Liver Forum: CHOLESTATIC · CHOLESTATIC ˜˚˛˝˙ˆˇˆ˙˛ ˘˜ ˆ ˝˘ President of...