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P. 102
Progression of liver disease in NAFLD
THE COURSE OF CIRRHOTIC NASH: HOW DIFFERENT
IS IT FROM OTHER CIRRHOSES
Arun J. Sanyal
Physiology and Molecular Pathology
Virginia Commonwealth University School of Medicine, The United States
E-mail: asanyal@mcvh-vcu.edu
Take home messages
• NASH progresses to cirrhosis in 15-20% of subjects.
• Multiple features of the MetS, abnormal ALT, increasing obesity and age, along with increasing
inflammation, ballooning and having some fibrosis, are risk factors for progression.
• The natural course of compensated NASH cirrhosis can be long; however, once decompensation
occurs the mortality is high.
• HCC can occur in NASH both in the presence and absence of cirrhosis.
• NASH is projected to become the leading indication for liver transplantation and also the leading
etiology of HCC.
Introduction
The pathophysiology, characteristics and public health importance of NAFLD and NASH are covered
elsewhere in this course. This syllabus focuses on the cirrhosis-linked outcomes in NASH and their
relationship to other common chronic liver diseases.
Rates of development of cirrhosis
Most cross-sectional studies have about 20% of subjects with bridging fibrosis or cirrhosis.Approximately
15-20% of subjects with NASH have been reported to progress to cirrhosis [1]. However, the available
literature is limited by its largely retrospective nature, the small number of subjects in individual studies
and ascertainment bias in many cases. The NIDDK NASH Clinical Research Network has provided
the first prospective data on progression of NASH. These data come from the longitudinal database
(which has selection bias because follow-up biopsies were not performed in all subjects in a protocol-
mandated manner) and from the control arms of the PIVENS and FLINT clinical trials (where such
biases did not exist, but bias due to participation in a clinical trial cannot be excluded). In the largest
study with paired biopsies from the CRN cohort, a total of 375 subjects were studied [2].Whereas those
without fibrosis at the initial biopsies did not progress to advanced fibrosis, an increasing number of
subjects with stage 1 and 2 disease, respectively, progressed to bridging fibrosis or cirrhosis. Elevated
ALT, presence of the MetS and the presence of some fibrosis as well as the severity of inflammation were
independent markers of progression.The PNPLA3 SNP associated with NAFLD is also associated with
both steatohepatitis and fibrosis stage [3]. The recently discovered TM6SF2 gene mutation has also
been linked, controversially, to more advanced disease [4].
Outcomes of cirrhosis related to NASH: a prospective study
Several small studies have provided data on the outcomes of cirrhosis due to NASH. The largest study
included 152 subjects with NASH related cirrhosis who were followed prospectively in a protocol-
102 Postgraduate Course Syllabus • Metabolic Liver Disease
THE COURSE OF CIRRHOTIC NASH: HOW DIFFERENT
IS IT FROM OTHER CIRRHOSES
Arun J. Sanyal
Physiology and Molecular Pathology
Virginia Commonwealth University School of Medicine, The United States
E-mail: asanyal@mcvh-vcu.edu
Take home messages
• NASH progresses to cirrhosis in 15-20% of subjects.
• Multiple features of the MetS, abnormal ALT, increasing obesity and age, along with increasing
inflammation, ballooning and having some fibrosis, are risk factors for progression.
• The natural course of compensated NASH cirrhosis can be long; however, once decompensation
occurs the mortality is high.
• HCC can occur in NASH both in the presence and absence of cirrhosis.
• NASH is projected to become the leading indication for liver transplantation and also the leading
etiology of HCC.
Introduction
The pathophysiology, characteristics and public health importance of NAFLD and NASH are covered
elsewhere in this course. This syllabus focuses on the cirrhosis-linked outcomes in NASH and their
relationship to other common chronic liver diseases.
Rates of development of cirrhosis
Most cross-sectional studies have about 20% of subjects with bridging fibrosis or cirrhosis.Approximately
15-20% of subjects with NASH have been reported to progress to cirrhosis [1]. However, the available
literature is limited by its largely retrospective nature, the small number of subjects in individual studies
and ascertainment bias in many cases. The NIDDK NASH Clinical Research Network has provided
the first prospective data on progression of NASH. These data come from the longitudinal database
(which has selection bias because follow-up biopsies were not performed in all subjects in a protocol-
mandated manner) and from the control arms of the PIVENS and FLINT clinical trials (where such
biases did not exist, but bias due to participation in a clinical trial cannot be excluded). In the largest
study with paired biopsies from the CRN cohort, a total of 375 subjects were studied [2].Whereas those
without fibrosis at the initial biopsies did not progress to advanced fibrosis, an increasing number of
subjects with stage 1 and 2 disease, respectively, progressed to bridging fibrosis or cirrhosis. Elevated
ALT, presence of the MetS and the presence of some fibrosis as well as the severity of inflammation were
independent markers of progression.The PNPLA3 SNP associated with NAFLD is also associated with
both steatohepatitis and fibrosis stage [3]. The recently discovered TM6SF2 gene mutation has also
been linked, controversially, to more advanced disease [4].
Outcomes of cirrhosis related to NASH: a prospective study
Several small studies have provided data on the outcomes of cirrhosis due to NASH. The largest study
included 152 subjects with NASH related cirrhosis who were followed prospectively in a protocol-
102 Postgraduate Course Syllabus • Metabolic Liver Disease
