William F. Balistreri, MD


April 08, 2016

In This Article

Editor's Note:
At The Liver Meeting®—the 66th annual meeting of the American Association for the Study of Liver Diseases—investigators highlighted the progress made in understanding common liver disorders, the availability of novel diagnostic and therapeutic options, and valid screening methodology to ensure optimal outcomes for patients. Some of the new approaches and concepts that emerged promise to alter the clinical practice of hepatology in the near future, and are reviewed herein.

Alpha-1 Antitrypsin Deficiency

In patients with alpha-1 antitrypsin deficiency (AATD), the pathologic accumulation of the misfolded alpha-1 antitrypsin Z (ATZ) protein in hepatocytes causes severe liver injury. It is necessary to define the risk for liver disease in these patients in order to direct screening and treatment toward those who could most benefit.

Liver Fibrosis in Adults With AATD but Without Overt Liver Disease

Clark and colleagues[1] tested the hypothesis that individuals with AATD have subclinical liver injury and fibrosis not detected by routine testing. To do so, they determined the prevalence and histologic spectrum of liver disease in 91 adults (mean age, 57 years; 61% female) with AATD who had a mean age of 45 years at diagnosis. Pulmonary symptoms were present at the time of AATD diagnosis in 64%, 28% were diagnosed because of a family member, and only 5% were identified because of an abnormal liver test.

The prevalence of clinically significant liver fibrosis, defined by an Ishak fibrosis score ≥ 2, was 35%. Men were more likely than women to have advanced fibrosis (22% vs 2%); AATD globule density correlated with the stage of fibrosis. This is higher than the previously reported fibrosis prevalence of approximately 8% using patient self-reported data. This study also confirmed that serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) levels in affected persons may fall within the reference range, which limits the clinical utility of these tests.

The risk factors and predictors for advanced liver disease are unknown, though Thompson and colleagues[2] identified three separate genetic variants that conferred susceptibility to liver disease in patients with AATD. The mechanisms by which this risk is conferred remain to be identified.

Liver-Specific Deletion of the Insulin Receptor Reduces Liver Injury

Chu and colleagues[3] determined that abrogation of insulin signaling, a key regulator of proteostasis mechanisms, reduces ATZ accumulation and proteotoxicity in a mouse model of AATD-associated liver disease. Histologic analysis of mouse livers depleted of the insulin receptor demonstrated a 60% reduction of intracellular ATZ globules and a 50% reduction in hepatic fibrosis. There was a significant increase in intracellular degradation of ATZ in insulin receptor knockout mice and complete elimination of nodular regeneration. These results indicate that the insulin signaling pathway suppresses a key mechanism by which the liver protects itself from misfolded ATZ via activation of the autophagolysosomal system.

The Search for a Therapeutic Agent

Wang and coworkers[4] set out to discover novel therapeutic drug candidates for AATD. They interrogated a Caenorhabditis elegans model of AATD (using genome-wide RNA interference screening and computational pharmacologic strategies) to identify genes that could modify the proteotoxicity of ATZ. They discovered over 100 genes that were potential positive modifiers, which were then analyzed as potential targets of known drugs, such as glyburide (glibenclamide), a sulfonylurea drug that has been used as an oral hypoglycemic agent.

Glyburide specifically and selectively mediated an increase in the rate of intracellular degradation of ATZ, inducing a marked decrease in levels of misfolded ATZ in a mammalian cell line model of AATD. This effect was dose- and time-dependent. Glyburide also reduced the hepatic ATZ load and hepatic fibrosis when administered systemically to a mouse model of AATD. Glyburide is therefore an appealing therapeutic drug candidate for AATD, in view of its wide margin of safety.


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