|
Customer Service 1-800-526-5224 |
Technical Service 1-800-447-3846 |
APOPTOSISKITS - M30 APOPTOSENSE® ELISA - ADDITIONAL BACKGROUND INFORMATION
Hepatocytes are involved in protein synthesis, protein storage and transformation of carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and detoxification, modification and excretion of exogenous and endogenous substances. Hepatocyte cell death by apoptosis is emerging as a fundamental component of virtually all acute and chronic liver diseases. The ensuing responses of cell repair, inflammation regeneration and fibrosis may all be triggered by apoptosis. Of these processes, hepatic fibrosis has the potential to be the most deleterious, as progressive fibrosis can culminate in cirrhosis.
Liver fibrosis results from chronic damage to the liver. Among the main causes
are viral hepatitis (i.e. hepatitis B
and C virus infection), alcoholic (ASH),
and non-alcoholic steatohepatitis (NASH).
An increasing body of evidence suggests that hepatocyte apoptosis may contribute
to liver fibrogenesis. Furthermore, recent studies in chronic HBV and HCV
infection as well as non-alcoholic fatty liver disease (NAFLD)
demonstrate that hepatocyte apoptosis correlates with disease activity.
Assessment of liver disease severity as well as monitoring chronic liver disease
over time remains a major challenge. Although liver biopsy is still considered
the gold standard for assessing disease activity, it is an invasive technique
with inherent risks that can be repeated only at infrequent intervals. It is
poorly suited to frequent monitoring because of its expense and morbidity, and
its accuracy suffers from sampling variation.
Noninvasive reliable tests to quantify the magnitude of hepatocyte apoptosis in humans, therefore, would be highly desirable, as serum biomarker for liver damage and for treatment response.
References:
The apoptotic pathway is composed of two arms: the intrinsic
pathway (initiated by cellular stress) and the extrinsic pathway (stimulated
through a death receptor–mediated process). Both pathways are suspected to be
involved in the pathogenesis of chronic inflammatory liver disease (CLD).
In the final common step of apoptosis, the effector caspases (in particular
caspase-3 and caspase-7) become activated. These specific intracellular
proteases are known to cleave several cellular substrates, including keratin 18
(K18, Cytokeratin 18 or K18), a major intermediate filament protein expressed by
hepatocytes. For selective detection of caspase-cleaved K18, a monoclonal
antibody (M30) was developed which have been shown to specifically label early
apoptotic hepatocytes but not cells of the immune system. Because liver is a
highly perfused organ, intracellular protein markers such as caspase-cleaved K18
are very likely to accumulate efficiently and rapidly in the blood. These
caspase-generated K18 fragments can be detected in the blood of subjects with
chronic inflammatory liver disease by using PEVIVA's M30 Apoptosense ELISA. The
caspase-specific cleavage product of keratin 18 is in particular advantageous as
K18 is abundant in hepatocytes, thereby providing specificity for the source of
this cleaved protein, and its caspase-mediated proteolytic cleavage of keratin
18 is specific to cell death by apoptosis with a favourable biological half life
in serum.
References:
Yoon JH, Gores GJ. Death receptor-mediated apoptosis and the liver. J Hepatol (2002) 37:400
An estimated 3% of the world’s population — more than 170 million
people — are infected by the hepatitis C virus (HCV). About 70% of infections
become chronic: a condition that is associated with developing end stage liver
disease such as cirrhosis and hepatocellular carcinoma (HCC). In subjects with
chronic HCV infection M30 values largely correlate with conventional surrogate
markers such as aminotransferase levels. However, subjects with normal ALT and
progressed HCV-related liver fibrosis were found to also have elevated
caspase-cleaved keratin 18 products in their serum, suggesting that M30
measurements represent an even more sensitive marker suitable for the detection
of early liver injury. Serological detection of caspase activity also mirrored
the degree of liver steatosis in those subjects. In addition, M30 is a reliable
serum marker to detect liver injury in subjects with chronic HBV infection.
Even with current antiviral treatment options about 50% of HCV subjects do not
respond to treatment, which is costly and associated with significant side
effects. There is a strong need for early detection of subjects that are not
responding to antiviral therapy. In a recent study it could be demonstrated that
HCV subjects responding to antiviral therapy revealed higher M30 serum levels
prior to treatment compared to non-responding subjects indicating that this
blood test could be a reliable biomarker assay for the prediction of treatment
response in subjects with different liver diseases.
References:
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of
liver abnormalities from benign steatosis to nonalcoholic steatohepatitis
(NASH). In line with the observation that M30 serum levels correlate with liver
steatosis in HCV-infected subjects, a recent study has shown that the extent of
caspase-cleaved K18 in serum correlates with the grade of liver steatosis in
subjects with NAFLD. Moreover, in this study measurement of M30 serum levels
allowed the discrimination between simple NAFLD and NASH and therefore, the
detection of subjects with increased risk of developing progressive (end stage)
liver disease. This assay may therefore represent a sensitive tool for the
identification of NASH subjects who should be monitored more closely with
respect to disease progression.
In summary, because of its high sensitivity, specificity, and positive and
negative predictive value, the M30 Apoptosense ELISA has the potential to become
an important noninvasive biomarker.
References:
| ORDER | © 1997-2011, DiaPharma Group, Inc. |