Integrated Approaches for Identifying Molecular Targets in Liver Disease
Condition: Alcoholic Liver Disease; Non-Alcoholic Fatty Liver Disease; Steatohepatitis, Nonalcoholic; Steatohepatitis
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Liver Diseases, Alcoholic
Study type: Observational

Summary: 
      To provide a framework for successful clinical trials testing novel targets for therapy in
      liver disease.

      To identify molecular and cellular drivers of liver disease to provide a molecular
      classification and study the determinants or key drivers of disease progression.

      Consecutive patients admitted with steatohepatitis (alcoholic or non-alcoholic) will be
      enrolled in this study where liver tissue, blood and stool will be collected to discover and
      validate factors associated with diagnosis, severity, histological characteristics,
      development of decompensations, progression of disease and survival.
    

Detailed description: 
      In 2015, chronic liver diseases were responsible for approximately 2% of worldwide mortality
      and in 2016 cirrhosis and chronic liver diseases accounted for 531.1 age- standardized,
      Disability Adjusted Life Years (DALY's) /100,000 habitants.(1, 2) Cirrhosis is a leading
      cause of death worldwide within adults between 50 and 70 years old. In the past few decades
      vast improvements have been made, death rates have decreased for almost all diseases.
      However, in the USA, the occurrence of alcoholic cirrhosis and HCV cirrhosis has increased,
      79 and 75% respectively, from 1990 to 2016 in regards of total number of deaths (3). This
      trend can also be observed in other countries such as UK where standardized mortality rates
      have increased 400% in the last 44 years. This has a big impact in the working-age population
      (18-65 years old)(4). The main causes of liver cirrhosis are hepatitis B virus (HBV) and C
      (HCV) as well as alcoholic and non-alcoholic fatty liver disease (ALD and NAFLD,
      respectively).

      Most chronic liver diseases have a silent course until the development of complications. For
      patients with compensated disease, the presence of significant liver fibrosis predicts
      decompensated disease and early mortality.(5-8) Therefore, diagnosis at early stages is
      mandatory to prevent liver-related morbidity and mortality.

      The aim of this project is to provide a framework for successful clinical trials testing
      novel targets for therapy in liver disease. The "Integrated Approaches for Identifying
      Molecular Targets in Liver Disease" (InLi) group is aimed to fill this gap. The group InLi
      will be composed of a multidisciplinary group including hepatologists, physician-scientists,
      basic scientists and bioinformatics experts. The main goal of InLi is to provide a framework
      for successful clinical trials testing novel targets for therapy in alcoholic hepatitis. The
      Human Biorepository Core will include a variety of biological samples from patients with a
      wide arrange of liver diseases as well as healthy controls from UPMC liver center as well as
      a comprehensive database that includes epidemiological, dietary, anthropometrical,
      analytical, histological, and clinical data.

      A common protocol for tissue processing, shipping and storage will be used to ensure sample
      integrity and quality. Storage of data generated from patients and biospecimens will be
      facilitated through, Research Electronic Data Capture (REDCap) system, and will follow strict
      security measures including encryption, coding and limited access to the database.

      The development of new-targeted therapies for most liver diseases, but especially,
      steatohepatitis, one of the more urgent needs in clinical hepatology. To reach this goal, a
      large multidisciplinary network is required. InLI coordinates a multidisciplinary group
      composed of clinicians, physician-scientists, basic scientists and bioinformatics experts.
      The overarching hypothesis of InLi is that the most rational way to provide a useful
      framework for future clinical trials in liver disease consists of the (i) determination of
      key drivers of the disease process, (ii) classification of molecular profiles and subtypes of
      specific liver diseases within each and every pathology, and (iii)identification of
      "druggable" targets based on both key drivers and molecular classification.

      The Human Biorepository Core will generate a large collection of samples from patients with
      different Liver diseases (e.g. viral, steatohepatitis and cholestasis liver disease). For
      each disease, we will consider a range of phenotypes focusing in early, intermediate and late
      disease stages and for each etiology. Moreover, we will also include samples from control
      patients. We will also build a comprehensive database that will serve as a basis for the
      proposed translational studies and be a valuable asset for the broader scientific community.

      The two scientific projects will combine a thorough molecular characterization of patients
      with different liver disease with studies on key and targetable pathways that drive key
      aspects of alcoholic hepatitis (AH) disease progression and outcome such as inflammation,
      injury and regeneration.

      Project 1: ("Molecular Subtypes for Targeted Therapies in Liver disease") will identify
      molecular and cellular drivers of liver disease to provide a molecular classification using
      RNA sequencing, kinomic, metabolomic and novel systems biology approaches, and determine
      contributors to unfavorable outcomes and the associated progenitor cell accumulation.

      Project 2: ("Determination of key drivers of the disease progression") The aim of the study
      is to describe histological, clinical and molecular characteristics that will make a
      particular disease evolve from early to advance form. We will use "omics" and novel systems,
      a biological approach as well as classic immunohistochemistry and histology stain technics.
      We will also use different imaging methodologies including second harmonic generation imaging
      microscopy (SHIM) and electronic microscopy to describe and identify specific histological
      patterns.

      Project 3: Build a Human repository capable of providing a platform to develop projects 1 and
      2.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        1. Alcoholic Steatohepatitis and Alcoholic liver disease

          2. Nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)
      
Biospecimen description: 
      -Serum, plasma, whole blood, urine, stool, liver tissue, visceral fat and saliva