Impact of Muscle Insulin Resistance on the Pathogenesis of Non Alcoholic Steatohepatitis
| Status: | Completed |
|---|---|
| Conditions: | Endocrine, Gastrointestinal |
| Therapuetic Areas: | Endocrinology, Gastroenterology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | December 2010 |
| End Date: | January 2016 |
Predictive Value of Inflammation and Fibrosis in Skeletal Muscle for Liver Histopathology in Patients With Non Alcoholic Fatty Liver Disease: Impact of Muscle Insulin Resistance on the Pathogenesis of Non Alcoholic Steatohepatitis
The incidence of Non alcoholic fatty liver disease (NAFLD) continues to increase, and
prevalence estimates for NAFLD range from 17-33%, making it is the most common cause of
chronic liver disease in North America. It is associated with increased cardiovascular
morbidity as well as progression to cirrhosis is a subset of patients. There is currently no
approved treatment for NAFLD. A key barrier to the development of effective therapies is a
lack of consensus on the criteria for diagnosis and endpoints for studies evaluating
diagnostic markers, prognosis and therapeutic modalities.
NAFLD encompasses an entire pathological spectrum of disease, from relatively benign
accumulation of lipid (steatosis) to progressive non alcoholic steatohepatitis (NASH)
associated with inflammation, fibrosis, and necrosis. It has been estimated that 20-30% of
patients with NAFLD will exhibit biochemical and histological changes characteristic of
NASH, and 15-20% of those patients will progress to have cirrhosis. NASH remains an
important phenotypic state, because this sub-group of patients is deemed at high-risk for
developing progressive disease resulting in cirrhosis, liver failure requiring
transplantation, or death.
Although NAFLD has not to date been included as a component of the metabolic syndrome, there
is increasing evidence that NAFLD frequently accompanies the development of insulin
resistance and therefore may be an indicator or predictor of future cardiometabolic risk.
Moreover, recent findings in skeletal muscle of experimental insulin resistance (lipid
infusion) as well as naturally occurring obese and type 2 diabetic, insulin resistant
patients show that skeletal muscle inflammation leads to a pattern of extracellular matrix,
structural, and remodeling abnormalities that closely resemble the TGFb, connective tissue
growth factor (CTGF) mediated fibrotic response that differentiates simple steatotic liver
from NASH. This suggests there may be a common underlying mechanism. Given the ready
availability of skeletal muscle tissue using percutaneous needle muscle biopsies, compared
to the more invasive liver biopsy, it may be possible to use characteristics of skeletal
muscle to distinguish the severity of liver fibrosis.
Given the preponderance of patients being identified with NAFLD, the recognition of less and
non invasive tests that help to discriminate the different phenotypic types of NAFLD would
be highly practical and useful. This would help identify patients at risk of progression to
cirrhosis, and thus make them the target of any available therapeutic interventions.
The investigators hypothesize that 1. Insulin resistance measured through glucose tolerance
test directly correlates with the extent of liver and muscle fibrosis, and 2. Inflammation
and fibrosis in the skeletal muscles correlates with the histopathological changes seen in
patients with NAFLD, and potentially skeletal muscle inflammation may be used as a
diagnostic predictor to differentiate patients with NASH from patients with simple
steatosis.
The overall goal of this project is to determine the extent to which inflammation and
fibrosis in skeletal muscle mirrors and is predictive of the level of liver inflammation and
can distinguish NASH from simple steatosis. Specifically, the investigators propose the
following Aims:
1. To use estimates of insulin sensitivity from modeling of oral glucose tolerance tests
to test the hypothesis that the extent of liver and muscle fibrosis is directly related
to insulin resistance.
2. To use liver and muscle biopsies to characterize the changes in abundance of mRNAs and
proteins that characterize inflammation, extracellular matrix remodeling, and fibrosis.
The investigators will use quantitative rt-PCR and immunoblot analysis to compare mRNA
expression and protein abundance of collagens I and III, fibronectin, and connective
tissue growth factor (CTGF) to test the hypothesis that there is a direct relationship
between the levels of these proteins in muscle and liver and the degree of fibrosis.
3. To establish a biospecimen repository of serum, mRNA from circulating white blood
cells, liver and muscle tissue, and DNA to serve as the substrate for future studies of
the pathogenesis of NASH.
prevalence estimates for NAFLD range from 17-33%, making it is the most common cause of
chronic liver disease in North America. It is associated with increased cardiovascular
morbidity as well as progression to cirrhosis is a subset of patients. There is currently no
approved treatment for NAFLD. A key barrier to the development of effective therapies is a
lack of consensus on the criteria for diagnosis and endpoints for studies evaluating
diagnostic markers, prognosis and therapeutic modalities.
NAFLD encompasses an entire pathological spectrum of disease, from relatively benign
accumulation of lipid (steatosis) to progressive non alcoholic steatohepatitis (NASH)
associated with inflammation, fibrosis, and necrosis. It has been estimated that 20-30% of
patients with NAFLD will exhibit biochemical and histological changes characteristic of
NASH, and 15-20% of those patients will progress to have cirrhosis. NASH remains an
important phenotypic state, because this sub-group of patients is deemed at high-risk for
developing progressive disease resulting in cirrhosis, liver failure requiring
transplantation, or death.
Although NAFLD has not to date been included as a component of the metabolic syndrome, there
is increasing evidence that NAFLD frequently accompanies the development of insulin
resistance and therefore may be an indicator or predictor of future cardiometabolic risk.
Moreover, recent findings in skeletal muscle of experimental insulin resistance (lipid
infusion) as well as naturally occurring obese and type 2 diabetic, insulin resistant
patients show that skeletal muscle inflammation leads to a pattern of extracellular matrix,
structural, and remodeling abnormalities that closely resemble the TGFb, connective tissue
growth factor (CTGF) mediated fibrotic response that differentiates simple steatotic liver
from NASH. This suggests there may be a common underlying mechanism. Given the ready
availability of skeletal muscle tissue using percutaneous needle muscle biopsies, compared
to the more invasive liver biopsy, it may be possible to use characteristics of skeletal
muscle to distinguish the severity of liver fibrosis.
Given the preponderance of patients being identified with NAFLD, the recognition of less and
non invasive tests that help to discriminate the different phenotypic types of NAFLD would
be highly practical and useful. This would help identify patients at risk of progression to
cirrhosis, and thus make them the target of any available therapeutic interventions.
The investigators hypothesize that 1. Insulin resistance measured through glucose tolerance
test directly correlates with the extent of liver and muscle fibrosis, and 2. Inflammation
and fibrosis in the skeletal muscles correlates with the histopathological changes seen in
patients with NAFLD, and potentially skeletal muscle inflammation may be used as a
diagnostic predictor to differentiate patients with NASH from patients with simple
steatosis.
The overall goal of this project is to determine the extent to which inflammation and
fibrosis in skeletal muscle mirrors and is predictive of the level of liver inflammation and
can distinguish NASH from simple steatosis. Specifically, the investigators propose the
following Aims:
1. To use estimates of insulin sensitivity from modeling of oral glucose tolerance tests
to test the hypothesis that the extent of liver and muscle fibrosis is directly related
to insulin resistance.
2. To use liver and muscle biopsies to characterize the changes in abundance of mRNAs and
proteins that characterize inflammation, extracellular matrix remodeling, and fibrosis.
The investigators will use quantitative rt-PCR and immunoblot analysis to compare mRNA
expression and protein abundance of collagens I and III, fibronectin, and connective
tissue growth factor (CTGF) to test the hypothesis that there is a direct relationship
between the levels of these proteins in muscle and liver and the degree of fibrosis.
3. To establish a biospecimen repository of serum, mRNA from circulating white blood
cells, liver and muscle tissue, and DNA to serve as the substrate for future studies of
the pathogenesis of NASH.
Inclusion Criteria:
Ability and willingness to give written, informed consent to be screened for and if
eligible to be enrolled in the study.
- Age > 18 years old.
- Minimal or no alcohol use (< 14 drinks/week in a man, < 7 drinks/week in a woman.
Approximately 10g of alcohol equals one drink unit. One drink unit equals 1 ounce of
distilled spirit, one 12-oz beer, or one 4-oz glass of wine.
- Collection of a standard of care liver biopsy that is obtained within 120 days of
enrollment.
- Collection of biosamples (serum, plasma, PMNC, muscle biopsy) within 90 days of
enrollment.
- NAFLD diagnosis based on standard clinical, imaging, and histological criteria.
Exclusion Criteria:
- Pregnant women.
- Age < 18 years old.
- Unable to consent for study.
- Patients who underwent liver transplant.
- Patients on oral steroids for more than 2 weeks within 6 months of enrollment.
- Patients with Diabetes Mellitus.
- Clinical or histological evidence of alcoholic liver disease: Regular and excessive
alcohol use within two years of enrollment: > 14 drinks/week in a man, >7 drinks/week
in a woman.
- Absence of any other liver disease: Autoimmune hepatitis, viral hepatitis, alpha-1
antitrypsin deficiency, hemochromatosis, drug induced liver injury, Wilson's disease,
or cholestatic liver disease.
- Known HIV.
- Hepatocellular carcinoma.
- History of bariatric surgery.
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