William F. Balistreri, MD

Disclosures

April 05, 2016

In This Article

Expanding Our Understanding of NAFLD/NASH

Noninvasive Fibrosis Detection Techniques

Magnetic resonance elastography (MRE) is an advanced imaging technique that has been shown to be accurate for diagnosing fibrosis in patients with NAFLD. However, this accuracy is offset by the fact that MRE is expensive and available only at specialized centers. Ultrasound-based imaging techniques, including acoustic radiation force impulse (ARFI) elastography, are cheaper and more widely available but may be less accurate than MRE.

Cui and colleagues[4] performed a prospective, head-to-head comparison of the diagnostic accuracy of MRE vs ARFI for diagnosing fibrosis in a well-characterized cohort of patients with NAFLD. MRE had a higher area under the receiver-operating characteristic curve than ARFI for discriminating fibrosis stages at every dichotomization cut point, but the difference was smaller as the cut point increased. Using contemporaneous liver biopsy as the gold standard, MRE provided significantly higher diagnostic accuracy than ARFI for diagnosing any degree of fibrosis in patients with NAFLD.

In another presentation, Wong and coworkers[5] reported on the use of liver stiffness measurements and serum-based FibroMeter tests in almost 300 patients with NAFLD. The FibroMeter score was valid in all patients. Liver stiffness at a cutoff of 7.9 kPa excluded significant fibrosis.

Modeling NAFLD/NASH

There is currently a lack of consistent models to mimic the clinical condition of NAFLD, as well as studies considering age and eventual gender differences.

To develop and characterize an NAFLD model, C57BL/6 mice were randomly assigned immediately after weaning to receive a control or a high-fat/high-carbohydrate diet, which induced significant body weight gain in both sexes.[6] Male mice developed hyperplasia of epididymal fat pads after 4 weeks, and significant hepatomegaly along with early alteration of glycemia, insulinemia, lipid profile, and ALT levels after 12 weeks. Similar body/blood alterations were observed in females, but only after the 16th week. Liver histology documented a mixed macro/microvesicular steatosis, which increased steadily after the eighth week. Both sexes developed progressive fibrosis starting from the eighth week.

This model might prove to be a useful tool to advance our understanding of the early stages of liver injury and provide insight into sex-related differences underlying these mechanisms.

Maintaining Intestinal Homeostasis

The G-protein–coupled chemokine receptor Cx3cr1, which serves as a gatekeeper for the intestinal barrier, has been shown to play a central role in many metabolic diseases, including type 2 diabetes, atherosclerosis, and obesity. Intestinal dysbiosis drives NASH development, and Cx3cr1 is essential for intestinal homeostasis.

Schneider and coworkers[7] hypothesized that Cx3cr1 plays a role in regulating the gut/liver axis and therefore has implications for progression of NASH. Compared with controls, Cx3cr1 deficient (knockout) mice on a high-fat diet showed severe hepatic steatosis and inflammation, as well as systemic glucose intolerance. Cx3cr1 deficiency in mice was also associated with significantly altered intestinal microbiota composition, which was linked to an impaired intestinal barrier, including thinner colonic mucus layers, reduction of tight junction expression, and a decrease in colonic resident phagocytic macrophages. Concomitantly, there was an enhanced inflammatory response in the liver.

Depletion of the intestinal microbiota by administration of broad-spectrum antibiotics suppressed the number of infiltrating macrophages. Consequently, antibiotic-treated mice demonstrated marked improvement of steatohepatitis and glucose tolerance.

These experiments suggest that microbiota-mediated activation of the innate immune responses via Cx3cr1 is crucial for controlling steatohepatitis progression, confirming the role of CX3CR1 as an essential gatekeeper regulating the gut barrier and homeostasis.

A Potential Link Between NAFLD and Hepatocellular Carcinoma

Wu and colleagues[8] investigated the role of microRNA-21 in the pathogenesis of NAFLD and its potential involvement in hepatocellular carcinoma (HCC). Wild-type mice maintained on a high-fat diet received tail-vein injections of microRNA-21 antisense oligonucleotide (ASO) or microRNA-21–mismatched ASO. Expression of microRNA-21 was increased in the livers of high-fat diet-treated mice. Knockdown of microRNA-21 impaired lipid accumulation and tumor growth.

Mechanistically, microRNA-21 knockdown induced p53 transcription, which subsequently reduced expression of genes controlling lipogenesis and cell cycle transition. In contrast, the opposite result was observed with overexpression of microRNA-21, which prevented p53 transcription.

These findings reveal a novel mechanism by which microRNA-21 in part promotes hepatic lipid accumulation and cancer progression, and suggest the potential therapeutic value of microRNA-21 ASO for both disorders.

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