NAFLD marker for mortality NAFLD is characterized by

NAFLD represents a continuum of liver
injury ranging from fatty infiltration affecting >5% of hepatocytes
(steatosis) to fatty infiltration in the presence of inflammation (NASH) with
or without fibrosis through to end-stage cirrhosis 1. In line
with the current obesity epidemic, there has been a substantial increase in the
prevalence of Non-alcoholic fatty liver disease (NAFLD). In Western nations
NAFLD affects approximately one third of the population and NASH cirrhosis is
predicted to be the primary aetiology for liver transplantation by 2020 2,

Variability in Disease Progression/fibrosis as a surrogate marker for mortality

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 NAFLD is characterized by
considerable interpatient variability in terms of rate of progression and
disease outcome. It is documented that although up to 25% of the general
population are at risk of progressive disease, only a minority experience
associated liver-related morbidity and progress to cirrhosis 1.
Paired biopsy studies, totalling approximately 400 patients, have examined the
histological evolution of steatosis, steatohepatitis and fibrosis in NAFLD
patients 4-13. In
general, it is thought that fibrosis progression in patients with NAFL is
uncommon, whereas NASH progresses more frequently 5,
6, 8-12. However,
this dogma has been challenged, with recent studies indicating that both
steatosis and NASH may progress to advanced liver disease and that the presence and severity of
fibrosis is the key histological determinant of long-term prognosis 4,
13-17. Thus we can conclude that NAFLD is a complex
disease trait where subtle inter-patient genetic variations and environment
interact to determine disease phenotype and progression (7).  In a recent systemic review and meta-analysis
by Dulai et al, it was clearly demonstrated that in patients with NAFLD,
all-cause mortality increases with increasing fibrosis stage, increasing at an
exponential rather than linear rate beyond F3 fibrosis 18


Need for a fibrosis Biomarker

The disease
trajectory of NAFLD remains highly variable, often nonlinear in progression,
and most dependent on the presence or absence of fibrosis as determined by
hepatic histology obtained from liver biopsy. Liver biopsy is the current gold
standard for diagnosing and staging fibrosis. In the real world setting, it is underutilized
due to the misjudged risk of complications and furthermore histology obtained is
subject to sampling error, while the pathology assessment of the degree of
liver fibrosis and the stage of disease often suffers from inter-observer variability
in interpretation. Therefore to date, the lack of a tractable, non-invasive
biomarker has significantly hampered routine patient care and clinical trial
enrichment and ultimately the much needed development of anti-fibrotic treatments.
A fibrosis biomarker thus has the potential to fulfil the diagnostic,
prognostic and dynamic goals of the ‘Burden of disease, Investigative,
Prognostic, Efficacy of intervention, and Diagnostic’ (BIPED) criteria as
recommended by the FDA BEST classification19.

Non-invasive tests in
current use

Non-invasive tests
for liver fibrosis have been validated in patients with NAFLD; however, none
have the accuracy to completely replace liver biopsy 20, 21. Their clinical utility is derived from their
high negative predictive value in excluding patients with advanced fibrotic
disease (>F3). However, the positive predictive values of these indices are
resoundingly unreliable and furthermore, McPherson et al recently demonstrated
that age is a significant confounding factor 
with the specificity for advanced fibrosis becoming  unacceptably low in patients aged ?65 years,
resulting in a high false positive rate. New thresholds for use in patients
aged ?65 years were derived to address this issue as it pertained to the NFS
and FIB 4 index 22. Broadly speaking fibrosis biomarkers can
be dichotomized into Simple non-invasive fibrosis scores derived from routine
clinical and biochemical indices, such as the aspartate aminotransferase
(AST)/alanine transaminase (ALT) ratio, fibrosis 4

 (FIB-4) score and NAFLD fibrosis score (NFS) 23-27 and complex fibrosis panels that include markers of
matrix turnover, such as the Enhanced Liver fibrosis panel and FibroTest 28, 29. Furthermore, the irregular distribution
of fibrosis through the liver indicates that such scoring systems may
potentially represent a more accurate reflection of global liver fibrosis. A Lancet
Commission addressing liver disease has recommended that simple non-invasive
scores be used to help identify patients with advanced fibrosis in the
community 30. As a result, these non-invasive scores
are now widely used “first line” in primary and secondary care to assess
fibrosis in patients with abnormal liver enzymes and suspected NAFLD 31.

Neo-epitope specific Biomarkers

In fibrogenesis,
both type I and type III collagen are integrated into ECM post cleavage of the
N- and C terminal pro-peptides. To date, PIIINP (N-terminal propeptide of type
III collagen) was exploited as a marker of both fibrogenesis and fibrolysis.
However, recent developments exploiting protein fingerprint technology has
resulted in the design of specific enzyme-linked immunosorbent assay (ELISA), that
assesses only formation but not degradation of type III collagen(By targeting
the N-protease cleavage site of PIIINP (Pro-C3) only) 32, 33. We hypothesis that the measurement of
formation neo-epitopes of type III collagen and subsequent generation of a
diagnostic panel could provide a better assessment of disease stage compared to
currently available biomarkers. Supporting this hypothesis is a recent study by
Leeming et al has shown that in NAFLD, 
elevated serum Pro-C3 is significantly associated with key components of
NAS and degree of liver fibrosis34. Other preliminary studies have
established Pro-C3 levels as indicative of active fibrogenesis therefore can
potentially identify patients most likely to benefit from anti-fibrotic
treatment and also play a role in monitoring of anti-fibrotic treatment effects