Sebastian Mueller, MD, PhD

 

Professor of Medicine,

CAR, University of Heidelberg 

 

VISCERA AG Bauchmedizin Bern 

 

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A better understanding of liver disease and the development of novel diagnostic tools and therapeutic approaches is in the center of our basic research and translational research activities. Below are some recent data from our group on the recently introduced novel paramter of liver stiffness which has drastically improved the diagnosis of chronic liver disease. Liver stiffness has also given novel inspirations for a better molecular understanding of liver cirrhosis, the major end-stage disease of all liver diseases that still cannot be treated causally and whose pathophysiology is still poorly understood. 

 

 

Selected topics

 

Controlled trials

  • First study worldwide to analyze hepatoprotective effect (liver stiffness) of Nalmefene (Selincro®) in patients with alcoholic liver disease (Study No.: 15871A, DELIVER, EudraCT: 2014-000413-31). More information on Nalmefene . Sponsored by Lundbeck. Recruitment till Summer 2015. Title: Exploratory, interventional, open-label, fixed-dose study with Selincro® as-needed use, in alcohol dependent patients with liver impairment  

 

 

 

Pilot studies

 

1. Improved algorithms for fibrosis assessment using liver stiffness 

2. Molecular mechanisms of liver stiffness  

3. Pressure-matrix hypothesis to explain liver cirrhosis

4. Genetics of liver cirrhosis and alcoholic liver disease

5. Liver stiffness and pregnancy together with Prof. H. Fluhr, Gynecology, University of Heidelberg

 

   

 

5. References liver fibrosis

6. References Liver stiffness 

7. References alcoholic liver disease

8. References Genetics

 

1. Diagnosis and Improved algorithms for fibrosis assessment using liver stiffness

 

The noninvasive quantitation of liver stiffness (LS) by ultrasound based transient elastography using FibroScan® has revolutionized the diagnosis of liver diseases, namely liver cirrhosis (reviewed in ref. 41). Alternative techniques such as acoustic radiation impulse frequency imagingsupersonic imaging or magnetic resonance elastography are currently under investigation. LS is an excellent surrogate marker of advanced fibrosis (F3) and cirrhosis (F4) outscoring all previous noninvasive approaches to detect cirrhosis. LS values below 6 kPa are considered as normal and exclude ongoing liver disease. LS of 8 and 12.5 kPa represent generally accepted cut-off values for F3 and F4 fibrosis. LS highly correlates with portal pressure, and esophageal varices are likely at values >20 kPa. Many other factors may also increase LS. We have proposed an validated interventional trials that 

 

a) the most important factors can be easily assessed by a routine abdominal ultasound prior to LS measurements (congestion, cholestasis, other spatial irregularities)

 

or

 

b) by transaminase levels (to estimate the degree of liver damage/inflammation 

 

c) that intervention (e.g. alcohol detoxification, treatment of congestive heart failure with diuretics etc.) will lower the liver stiffness which then even better reflects the true fibrosis stage.

Our actual practiced algorithm is shown below.

 

FIg. 1 

 

 

2. Molecular mechanisms of liver stiffness (LS)

 

Our group has extensively studied factors other than fibrosis that affect liver stiffness. Thus, we were able to show that liver congestion  and cholestasis can drastically increase liver stiffness irrespective of the fibrosis degree. Thus, LS should always be interpreted in the context of clinical, imaging and laboratory findings. In addition, we could recently show that liver stiffness can also be determined in the presence of ascites using transient elastography. This allows rapid identification of patients with non-hepatic causes of ascites. Our recent data also suggest that liver stiffness much better reflects liver function as thought so far. 

 

Fig. 2

 

3. Pressure-matrix hypothesis to explain liver cirrhosis

 

Together with L. Sandrin, we have developed the novel pressure-stiffness-matrix hypothesis to explain liver cirrhosis (presented in ref. 41). Fig. 3 below schematically shows the principle. We believe that all liver disease whether it is inflammation, congestion, cholestasis etc. lead to increased sinusoidal pressure either by cellular volume increase, osmotic or hydrostatic pressure. This pressure increases shear forces on stellate cells their actual signal for collagen depostion. We postulate further that the secreted matrix corresponds to the pressure in terms of time and intensity. Liver stiffness is ultimately the results of increased pressure or/and matrix deposition.

 

Fig. 3 

 

 

 

4. Genetics of liver cirrhosis and alcoholic liver disease

 

We are highly interested in a better understanding of the genetic modifies of fibrosis progression. Various studies are under way within several cooperations.

 

Link: international GWAS consortium on liver disease

 

 

5. References Liver stiffness

 

56.       Systemic mastocytosis – a rare case of increased liver stiffness
Stefanie Adolf, Gunda Millonig, H. K. Seitz, Andreas Reiter, Peter Schirmacher, Thomas Longerich, and Sebastian Mueller
Case Reports in Hepatology, vol. 2012, Article ID 728172, 6 pages, 2012. doi:10.1155/2012/728172 Received 2 September 2012; Accepted 19 September 2012

 

 

54.       Association of Liver Stiffness with Hepatic Expression of Pharmacokinetically Important Genes in Alcoholic Liver Disease.

Theile D, Haefeli WE, Seitz HK, Millonig G, Weiss J, Mueller S.

Alcohol Clin Exp Res. 2012 Jul 24. doi: 10.1111/j.1530-0277.2012.01901.x. [Epub ahead of print]

PMID: 22827451 [PubMed - as supplied by publisher]

Related citations

 

52.          EASL Clinical Practical Guidelines: Management of Alcoholic Liver Disease.

European Association For The Study Of The Liver.

J Hepatol. 2012 May 25. [Epub ahead of print] No abstract available.

PMID: 22633836 [PubMed - as supplied by publisher]

Related citations

 

51.          Transient elastography with the XL probe rapidly identifies patients with non-hepatic ascites.  
Kohlhaas, A.; Durango, E.; Millonig, G.; Bastard, C.; Sandrin, L.; Golriz, M.; Mehrabi, A.; Büchler, M. W.; Seitz, H. K.; Mueller, S. Hepatic Medicine: Evidence and Research 4:11-18; 2012.

 

47.          Transient micro-elastography: A novel non-invasive approach to measure liver stiffness in mice. 

Bastard C, Bosisio MR, Chabert M, Kalopissis AD, Mahrouf-Yorgov M, Gilgenkrantz H, Mueller S, Sandrin L.

World J Gastroenterol. 2011 Feb 28;17(8):968-75. Free PMC Article Related citations

 

41.          Liver stiffness: a novel parameter for the diagnosis of liver disease

Sebastian Mueller, Laurent Sandrin

Hepatic Medicine: Evidence and Research Published Date May 2010 , Volume 2010:2 Pages 49 - 67

 

38.          Increased liver stiffness in alcoholic liver disease: Differentiating fibrosis from steatohepatitis.

Mueller S, Millonig G, Sarovska L, Friedrich S, Reimann FM, Pritsch M, Eisele S, Stickel F, Longerich T, Schirmacher P, Seitz HK.

World J Gastroenterol. 2010 Feb 28;16(8):966-72.PMID: 20180235 [PubMed - in process]  Related articlesFree article

 

35.          Liver stiffness is directly influenced by central venous pressure.

Millonig G, Friedrich S, Adolf S, Fonouni H, Golriz M, Mehrabi A, Stiefel P, Pöschl G, Büchler MW, Seitz HK, Mueller S.

J Hepatol. 2009 Dec 4. [Epub ahead of print]PMID: 20022130 [PubMed - as supplied by publisher] Related articles

 

26.          Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis.

Millonig G, Reimann FM, Friedrich S, Fonouni H, Mehrabi A, Büchler MW, Seitz HK, Mueller S.

Hepatology. 2008 Nov;48(5):1718-23. PMID: 18836992 [PubMed - indexed for MEDLINE] Related Articles

   

 

Genetics

46.          Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians.

Stickel F, Buch S, Lau K, Zu Schwabedissen HM, Berg T, Ridinger M, Rietschel M, Schafmayer C, Braun F, Hinrichsen H, Günther R, Arlt A, Seeger M, Mueller S, Seitz HK, Soyka M, Lerch M, Lammert F, Sarrazin C, Kubitz R, Häussinger D, Hellerbrand C, Bröring D, Schreiber S, Kiefer F, Spanagel R, Mann K, Datz C, Krawczak M, Wodarz N, Völzke H, Hampe J.

Hepatology. 2011 Jan;53(1):86-95. doi: 10.1002/hep.24017. Epub 2010 Dec 7.PMID: 21254164 [PubMed - in process]Related citations

 

34.          [Hereditary hyperferritinemia cataract syndrome--the first family in Germany]

Millonig G, Holzer MP, Tolle G, Auffarth GU, Muckenthaler MU, Seitz HK, Mueller S.

Z Gastroenterol. 2009 Dec;47(12):1211. German. PMID: 19994473 [PubMed - in process] Related articles

   

28.          Alcohol and colorectal cancer: the role of alcohol dehydrogenase 1C polymorphism.

Homann N, König IR, Marks M, Benesova M, Stickel F, Millonig G, Mueller S, Seitz HK.

Alcohol Clin Exp Res. 2009 Mar;33(3):551-6. Epub 2008 Dec 19.

PMID: 19120062 [PubMed - indexed for MEDLINE] Related Articles

   

29.          In vitro-targeted gene identification in patients with hepatitis C using a genome-wide microarray technology.

Hagist S, Sültmann H, Millonig G, Hebling U, Kieslich D, Kuner R, Balaguer S, Seitz HK, Poustka A, Mueller S.

Hepatology. 2009 Feb;49(2):378-86.

PMID: 19177570 [PubMed - indexed for MEDLINE] Related Articles

   

 

References liver fibrosis

 

54.       Association of Liver Stiffness with Hepatic Expression of Pharmacokinetically Important Genes in Alcoholic Liver Disease.

Theile D, Haefeli WE, Seitz HK, Millonig G, Weiss J, Mueller S.

Alcohol Clin Exp Res. 2012 Jul 24. doi: 10.1111/j.1530-0277.2012.01901.x. [Epub ahead of print]

PMID: 22827451 [PubMed - as supplied by publisher]

Related citations

 

49.        Cannabinoid Receptor Type I Modulates Alcohol-Induced Liver Fibrosis.  
Patsenker E, Stoll M, Millonig G, Agaimy A, Wissniowski T, Schneider V, Mueller S, Brenneisen R, Seitz HK, Ocker M, Stickel F. Mol Med. 2011 Aug 19. doi: 10.2119/molmed.2011.00149. [Epub ahead of print] PMID:21863215 Free Article Related citations

 

46.          Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians.

Stickel F, Buch S, Lau K, Zu Schwabedissen HM, Berg T, Ridinger M, Rietschel M, Schafmayer C, Braun F, Hinrichsen H, Günther R, Arlt A, Seeger M, Mueller S, Seitz HK, Soyka M, Lerch M, Lammert F, Sarrazin C, Kubitz R, Häussinger D, Hellerbrand C, Bröring D, Schreiber S, Kiefer F, Spanagel R, Mann K, Datz C, Krawczak M, Wodarz N, Völzke H, Hampe J.

Hepatology. 2011 Jan;53(1):86-95. doi: 10.1002/hep.24017. Epub 2010 Dec 7.PMID: 21254164 [PubMed - in process]Related citations

   

41.          Liver stiffness: a novel parameter for the diagnosis of liver disease

Sebastian Mueller, Laurent Sandrin

Hepatic Medicine: Evidence and Research Published Date May 2010 , Volume 2010:2 Pages 49 - 67

 

38.          Increased liver stiffness in alcoholic liver disease: Differentiating fibrosis from steatohepatitis.

Mueller S, Millonig G, Sarovska L, Friedrich S, Reimann FM, Pritsch M, Eisele S, Stickel F, Longerich T, Schirmacher P, Seitz HK.

World J Gastroenterol. 2010 Feb 28;16(8):966-72.PMID: 20180235 [PubMed - in process]  Related articlesFree article

   

 

References alcoholic liver disease

 

54.       Association of Liver Stiffness with Hepatic Expression of Pharmacokinetically Important Genes in Alcoholic Liver Disease.

Theile D, Haefeli WE, Seitz HK, Millonig G, Weiss J, Mueller S.

Alcohol Clin Exp Res. 2012 Jul 24. doi: 10.1111/j.1530-0277.2012.01901.x. [Epub ahead of print]

PMID: 22827451 [PubMed - as supplied by publisher]

Related citations

 

52.          EASL Clinical Practical Guidelines: Management of Alcoholic Liver Disease.

European Association For The Study Of The Liver.

J Hepatol. 2012 May 25. [Epub ahead of print] No abstract available.

PMID: 22633836 [PubMed - as supplied by publisher]

Related citations

 

49.        Cannabinoid Receptor Type I Modulates Alcohol-Induced Liver Fibrosis.  
Patsenker E, Stoll M, Millonig G, Agaimy A, Wissniowski T, Schneider V, Mueller S, Brenneisen R, Seitz HK, Ocker M, Stickel F. Mol Med. 2011 Aug 19. doi: 10.2119/molmed.2011.00149. [Epub ahead of print] PMID:21863215 Free Article Related citations

 

46.          Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians.

Stickel F, Buch S, Lau K, Zu Schwabedissen HM, Berg T, Ridinger M, Rietschel M, Schafmayer C, Braun F, Hinrichsen H, Günther R, Arlt A, Seeger M, Mueller S, Seitz HK, Soyka M, Lerch M, Lammert F, Sarrazin C, Kubitz R, Häussinger D, Hellerbrand C, Bröring D, Schreiber S, Kiefer F, Spanagel R, Mann K, Datz C, Krawczak M, Wodarz N, Völzke H, Hampe J.

Hepatology. 2011 Jan;53(1):86-95. doi: 10.1002/hep.24017. Epub 2010 Dec 7.PMID: 21254164 [PubMed - in process]Related citations

 

45.          Ethanol-mediated carcinogenesis in the human esophagus implicates CYP2E1 induction and the generation of carcinogenic DNA-lesions.

Millonig G, Wang Y, Homann N, Bernhardt F, Qin H, Mueller S, Bartsch H, Seitz HK.

Int J Cancer. 2011 Feb 1;128(3):533-40.PMID: 20715111 [PubMed - indexed for MEDLINE]Related citations

   

38.          Increased liver stiffness in alcoholic liver disease: Differentiating fibrosis from steatohepatitis.

Mueller S, Millonig G, Sarovska L, Friedrich S, Reimann FM, Pritsch M, Eisele S, Stickel F, Longerich T, Schirmacher P, Seitz HK.

World J Gastroenterol. 2010 Feb 28;16(8):966-72.PMID: 20180235 [PubMed - in process]  Related articlesFree article

 

33.          Current Experimental Perspectives on the Clinical Progression of Alcoholic Liver Disease.

Breitkopf K, Nagy LE, Beier JI, Mueller S, Weng H, Dooley S.

Alcohol Clin Exp Res. 2009 Jul 23. [Epub ahead of print]

PMID: 19645734 [PubMed - as supplied by publisher] Related Articles

 

32.          Alcoholic liver disease and hepatitis C: a frequently underestimated combination.

Mueller S, Millonig G, Seitz HK.

World J Gastroenterol. 2009 Jul 28;15(28):3462-71.

PMID: 19630099 [PubMed - in process] Related Articles Free article in PMC | at journal site

 

31.          Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease.

Wang Y, Millonig G, Nair J, Patsenker E, Stickel F, Mueller S, Bartsch H, Seitz HK.

Hepatology. 2009 Aug;50(2):453-461. PMID: 19489076 [PubMed - as supplied by publisher] Related Articles

 

28.          Alcohol and colorectal cancer: the role of alcohol dehydrogenase 1C polymorphism.

Homann N, König IR, Marks M, Benesova M, Stickel F, Millonig G, Mueller S, Seitz HK.

Alcohol Clin Exp Res. 2009 Mar;33(3):551-6. Epub 2008 Dec 19.

PMID: 19120062 [PubMed - indexed for MEDLINE] Related Articles