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Pharmacology

Non-alcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)

2018-08-20
18808
Kunming, China, August 20, 2018

Nonalcoholic fatty liver disease (NAFLD)is a common liver disorder that represents the hepatic manifestation of the metabolic syndrome, an aggregate of disorders of obesity, insulin resistance, type II diabetes, hypertension and hyperlipidemia.  NAFLD is considered as a spectrum of histopathological abnormalities of the liver, ranging from simple steatosis (i.e., fatty liver) to nonalcoholic steatohepatitis or NASH.  NASH is regarded as a more aggressive form of liver injury that carries a risk for progressive fibrosis, cirrhosis, and end-stage liver disease, and is thus deemed to result in significant morbidity and mortality.  Histologically, NASH is characterized by the presence of inflammatory foci of mixed cell population, hepatocellular ballooning degeneration in addition to steatosis. Liver fibrosis can also be present as a consequence of hepatocyte damages.  In the most severe state, NASH may be associated with cirrhosis and hepatocyte carcinoma (HCC) in humans.


Progression to NASH has been observed among 20% to 30% of patients with nonalcoholic fatty liver (NAFL, simple steatosis), and the transition from NAFL to NASH has been considered to involve disruption of multiple compensatory pathways within the liver. Nevertheless, recent investigations argue that NAFL and NASH are likely distinct not only histologically but also pathophysiologically. Different animal models have so far been investigated and utilized in order to gain valuable insights in the mechanisms involved in NAFLD and NASH development. In order to facilitate target identification, efficacy assessment and biomarker development, it is critical to develop a translatable animal model that more closely recapitulates the etiology, risk factors, clinical and histopathological presentations of NASH in humans.


Male cynomolgus monkeys fed high fat diet longer than 2 years are first screened for metabolic disorders including obesity, dyslipidemia, insulin resistance, diabetes and hypertension. Monkeys that show dysfunctions in 2 or more metabolic components are then selected for liver biopsy (Figures 1&2).  Hepatic lesions are assessed histopathologically using the system established by NASH Clinical Research Network (Table 1). NASH is defined as the presence of steatosis, lobular inflammation and hepatocyte ballooning with NFALD activity scores of 4 or above (Figure 3). Liver fibrosis is determined by assessing the biopsy specimens stained with Sirius Red (Figure 4). About 60% of the monkeys with metabolic syndrome develop NASH and 30% of the NASH monkeys exhibit liver fibrosis.


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Development of non-invasive technologies for the assessment of NASH lesions represents the direction of the field. At KBI, we assess liver stiffness by elastography (Figure 5), liver fat by MRI-derived proton density fat fraction (MRI-PDFF, Figure 6) and liver fibrosis by measuring extracellular volume (ECV) using MRI T1 mapping (Figures 7&8).


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In addition to the relatively abundant animal sources, KBI is able to accommodate our clients’ different study goals and designs by providing sufficient NASH animals at different grades and stages. The state-of-art imaging technology available at KBI enables our clients to monitor the NASH lesion progression/regression in a noninvasive manner.


By collaborating with international pharmaceutical and biotech companies, KBI has studied a number of investigational drugs in our NHP NASH/fibrosis model including FGF21 and GLP-1 agonists that have exhibited efficacy and good safety profile in clinical trials.


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