Subproject 4: Specification and Documentation of Metabolic and Neoplastic Diseases

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M. Trauner, Division of Gastroenterology and Hepatology,

Department of Internal Medicine, MUG

Co- Investigator: H. Samonigg, Division of Oncology, Department of Internal Medicine, MUG

Subproject 4:

Specification and Documentation of Metabolic

and Neoplastic Diseases

Subproject 4:

Specification and Documentation of Metabolic

and Neoplastic Diseases

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Ein Programm des Programmmanagement: Wissenschaftskommunikation:

Associate prospectively collected human tissue and blood samples with detailed patient information

- Clinical presentation, disease course & outcome

- Family history, life style, additional diseases, medication

Cross-validate mouse models and corresponding human diseases

- Metabolic liver diseases and liver cancer

Project aims

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Metabolism (obesity, diabetes, iron) & cancer - Liver, breast, colorectal, …

Chronic inflammatory liver / bowel disease

cancer (end of a spectrum)

- Fatty liver – steatohepatitis – cirrhosis – HCC - Chronic hepatitis – cirrhosis – HCC

- Ulcerative colitis – dysplasia / DALM - CRC Underlying liver / GI disease + cancer

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NAFLD: Spectrum of Hepatic Pathology

Steatosis

Steato-hepatitis

Cirrhosis

HCC

Chronic metabolic liver disease leading to cancer

Modified after: A. M. Diehl, AGA Slide Series

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Prospective collection of medical data and sera of patients undergoing liver and intestinal biopsies

Serum samples from liver outpatients before, during and after therapy (including LTx)

Serum samples from cancer outpatients before, during and after medical / surgical therapy

Prospective collection & annotation

of patient samples

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Lifestyle and family questionnaire

Liver and oncology outpatient clinic

Number of pages: 16, option for automatic scanning Time effort: 30 min for patients and 10 min for M.D. Patient acceptance: very high (99%)

Personal and medical history:

- Nutrition (3 pages)

- Alcohol / nicotine consumption (2 p)

- Physical activity (3 p, collaboration with Institute of Sports Medicine) - Past medical history (2 p)

- Family history (5 p) - Medication (1 p)

Number of life style questionnaires

- Liver outpatient clinic: 105105

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Prospective collection of serum und tissue samples → consistent SOPs Centralized sample management

Actual number of tissue samples: 223223

- 87 liver biopsies (23 chronic viral hepatitis, 11 fatty liver, 12 steatohepatitis, 11 cholestatic liver disease, 7 autoimmune hepatitis, 23 other etiology)

- 136 intestinal biopsies (31 Crohn’s disease, 19 ulcerative colitis, 9 normal controls, 77 other etiology)

Actual number of serum samples: 18.45718.457

- 427 non-neoplastic liver diseases (viral, cholestatic, metabolic) - 35 hepatocellular carcinomas

- 18.013 non-hepatic cancers (3.488 colon, 1.796 rectal, 12.729 breast)

Merging of clinical und molecular data

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Associate prospectively collected human tissue and blood samples with detailed patient information

Cross-validate mouse models and corresponding human diseases

- Metabolic liver diseases and liver cancer

Project aims

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PL Mdr2 Bsep

X

X Abcg5/8 Cholesterol X Bile

Bile acidsacids

AE2

Cftr Cl

-Cl

-HCO₃

-MDR3 Mutations

-PFIC3 (progressive familial

intrahepatic cholestasis)

-Sclerosing cholangitis

-Intrahepatic cholestasis of pregnancy -Intrahepatic cholelithiasis

-Drug induced cholestasis -Adult biliary cirrhosis BD

BD

Fickert et al, Gastroenterology, 2002

Cross-validation of mouse models for

metabolic liver diseases & liver cancer

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Morphological Characterization of Hepatic Carcinogenesis in the Mdr2-/- Mouse Model

Department of Internal Medicine Division of Gastroenterology and Hepatology, Medical University of Graz

Departement of Pathology, Medical University Graz

Chromosomal instability in tumor development in Mdr2-/- mice

Departement of Medical Biology and Genetics, Medical University Graz

Effects of 24-nor-UDCA in a hepatocellular carcinoma xenograft nude mouse model

Departement of Pathology, Medical University Graz

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Side-chain-modification critically determines the physiologic and therapeutic

properties of 24-norUrsodeoxycholic Acid in the treatment of sclerosing cholangitis in

Mdr2 (Abcb4) Knockout Mice

Emina Halilbasic 1_{, Peter Fickert}1_{, Romina Fiorotto}2_{, Hanns-Ulrich Marschall} 3_{, Tarek}

Moustafa 1_{, Andrea Fuchsbichler}4_{, Judith Gumhold}1_{, Dagmar Silbert}1_{, Kurt Zatloukal}4_,

Cord Langner 4_{, Uday Maitra} 5_{, Helmut Denk4, Mario Strazzabosco}2_,

and Michael Trauner 1

1 _{Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and}

Hepatology, Department of Medicine, Medical University Graz, Austria; 2 _{Section of}

Digestive Diseases, Department of Internal Medicine, School of Medicine, Yale University, New Haven, USA; 3 _{Karolinska University Hospital Huddinge, Stockholm, Sweden;}4

Institute of Pathology, Medical University Graz, Austria; 5 _{Departement of Organic}

Chemistry, Indian Institute of Science, Bangalore, India

Hepatology 2009;49(6):1972-81.

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nor

norUDCAUDCA

PL

x

Differences in HCO₃--rich Hypercholeresis Cholehepatic Shunting Mdr2 -/-T

T--nornorUDCAUDCA bis

bis--nornorUDCAUDCA

HCO₃

-norUDCA as novel treatment for chronic

liver injury and biliary fibrosis in Mdr2

-/-

mouse model

Halilbasic et al., Hepatology, 2009 Anti-infammatory

Anti-fibrotic Anti-proliferative

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PL Mdr2 Bsep Abcg5/8 Cholesterol Bile

Bile acidsacids

AE2

Cftr Cl

-Cl

-HCO₃

-Cross-validation of mouse models for

metabolic liver diseases & liver cancer

X

WT Mdr2-/- _{Mdr2/FXR DKO}

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Prospective collection of human tissue and blood

samples with detailed clinical data from patients with metabolic and neoplastic disorders

Cross-validation of corresponding mouse models

Summary

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