Liver Disease From Alpha-1-Antitrypsin Deficiency

What Therapeutic Options Are in the Pipeline?

David H. Perlmutter, MD; Andrew Chu, MD; Kapil B. Chopra, MD


February 04, 2015


Are there therapeutic options other than liver transplantation for severe liver disease due to alpha-1-antitrypsin deficiency?

Response from:
David H. Perlmutter, MD
, Vira I. Heinz Endowed Chairman, Department of Pediatrics, Distinguished Professor of Pediatrics, Professor of Cell Biology, University of Pittsburgh School of Medicine; Physician-in-Chief, Scientific Director, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Andrew Chu, MD, Assistant Professor of Pediatrics, University of Pittsburgh School of Medicine; Attending Physician, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Kapil B. Chopra, MD, Associate Professor, Department of Medicine, University of Pittsburgh School of Medicine; Medical Director, Comprehensive Liver Program, University of Pittsburgh Medical Center Liver Pancreas Institute, Pittsburgh, Pennsylvania

The liver disease caused by alpha-1-antitrypsin deficiency (ATD) is predominantly characterized by fibrosis/cirrhosis with relatively limited inflammation and an increased likelihood of hepatic carcinoma. These effects are caused by the "proteotoxicity" of a misfolded protein that accumulates in liver cells.[1] Although ATD is well known to cause liver disease in pediatric patients, more than 85% of liver transplants in the United States are done for adult patients with ATD, with peak age range of 50-65 years.[2]

Liver transplantation is the only therapeutic option currently available for progressive liver disease in patients with ATD. The latest studies show that liver transplantation results in 5-year survival rates of 90% for children and greater than 80% for adults.[3] However, several new strategies have evolved from animal studies. Below we describe our clinical trial investigating a new class of drugs that could reduce the need for liver transplantation and/or help patients who are not ideal candidates for liver transplantation.

But first it is important to mention that ATD liver disease can be slowly progressive. Indeed, when Eriksson and colleagues[4] first described the association of cirrhosis and hepatocellular carcinoma, they noted that this pathology was mainly found incidentally at autopsy in ATD patients who had died from other causes. This means that some patients with relatively mild portal hypertension at diagnosis can be observed for a period of time before liver transplantation becomes necessary, and perhaps this also represents a window for new strategies to prevent progression of the disease. Other patients with portal hypertension will require the usual management approaches for associated complications, including variceal bleeding, ascites, encephalopathy, and the consequences of hypersplenism.[5]

Although the true incidence of hepatic carcinoma in ATD is not known,[4,6] our anecdotal experience has identified a relatively high incidence of hepatocellular carcinoma and cholangiocarcinoma; we strongly recommend MRI of the liver and biliary system at the time of diagnosis or shortly thereafter, and monitoring of serum alpha-fetoprotein (AFP) levels thereafter.

In 2010 we published a report[7] showing that carbamazepine, an anticonvulsant and mood stabilizer, could stimulate intracellular degradation of the misfolded alpha-1-antitrypsin. By reducing the proteotoxic accumulation, this drug reversed fibrosis in a mouse model of ATD.[7] Since then, we have discovered several other drugs that have the property of enhancing degradation of misfolded alpha-1-antitrypsin in the liver.[8,9,10] Most important, some of these drugs are approved by the US Food and Drug Administration and used relatively frequently in clinical medicine, so they can be moved immediately into phase 2/3 clinical trials.

We are testing carbamazepine for safety and efficacy in patients with severe liver disease due to ATD. Our phase 2/3 trial is a double-blind, placebo-controlled design targeting patients with the ZZ or SZ phenotype who have signs of portal hypertension. In addition to monitoring for safety, we are using histologic features, hepatic wedge pressure gradient, and magnetic resonance elastography to evaluate efficacy. We need another 14 subjects to complete this current trial and will soon be starting a new trial to determine whether this drug strategy can arrest progression to prevent portal hypertension.

Because ATD is a rare disease, it is very challenging to recruit enough subjects for these trials. Please consider referring us your patients with ATD. You can reach us by email or by phone at 412-692-6558.


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