MMDx-Liver System

Investigators: Dr. Philip F Halloran, and the MMDx-Liver Study Group ( NCT03193151)

INTERLIVER ( NCT03193151) is a prospective observational study of the relationship of the molecular phenotype of 300 liver transplant biopsies, performed as standard-of-care for indications or by center protocol, to the histologic phenotype and the clinical features and outcomes. Part of one liver transplant biopsy core with accompanying data will be sent to the ATAGC for analysis; a report format will be developed, and all biopsies will be reported to the center investigator.

Goals: to change care and outcomes in liver transplantation through molecular diagnostics


Liver transplantation is a remarkable success story in managing end-stage liver disease, until recently heavily impacted by the influence of hepatitis C virus (HCV) which confused assessment of rejection. The emerging cures for HCV have created a new agenda for liver transplantation: improve understanding and diagnosis of T cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR), and injury/fibrosis. Liver transplant management, however, presents a special case of a general problem: the unsatisfactory state of biopsy assessment by histology.

There is a strong belief that this will require new molecular diagnostic support using the liver transplant biopsies. The prime choice is the microarray analysis of global gene expression by microarrays. Protein coding mRNAs have the diversity and richness in annotation to fully define disease mechanisms.

Why study molecules?

  1. Mechanisms (not just "biomarkers")
  2. New tests
  3. International standard
  4. Recalibrate conventional tests
  5. Guide and monitor response to therapy
  6. Empower clinical trials


  1. Liver transplant biopsies can be assessed by microarrays, adapting the Molecular Microscope® Diagnostic System (MMDx) recently developed by the ATAGC for kidney, heart, and lung transplant biopsies.
  2. Molecular phenotyping will create a precision diagnostic system for liver transplant, with accurate assessments to guide patient management decisions and support therapeutic decisions.
  3. If histology is not necessary, MMDx requires less tissue.
  4. The experience with rejection and injury syndromes in kidney, heart, and lung can guide a "fast track" approach to liver biopsies.
  5. The lessons learned about injury and fibrosis in liver transplant biopsies will be applicable to biopsies from primary liver diseases.

Goals: to change care and outcomes in liver transplantation

  1. To create a centralized MMDx system for interpretation of liver transplant biopsies.
  2. To assess the diagnostic and prognostic value of microarray analysis of biopsy specimens from liver allografts, and define the molecular phenotype of liver biopsy.
  3. To develop microarray-based tests for liver biopsy specimens for the TCMR, ABMR, and acute and chronic liver injury.
  4. To compare microarray analysis of liver allograft biopsy specimens to conventional allograft phenotyping, including clinical, physiologic, radiographic, ultrasound and histological assessment.

MMDx-Liver Publications:

  1. Madill-Thomsen K, Abouljoud M, Bhati C, Ciszek M, Durlik M, Feng S, et al. The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study. Am J Transplant. 2020;20(8):2156-72.
  2. Madill-Thomsen KS, Abouljoud M, Bhati C, Ciszek M, Durlik M, Feng S, et al. The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study. Am J Transplant. 2022;22(3):909-26.