Two New Considerations for Improving the Diagnosis of α1-Antitrypsin Deficiency-Associated Liver Disease

Excerpt

The study by Tapper et al. [1], published in this issue of Digestive Diseases and Sciences, rather starkly emphasizes the need for improvements in clinical practice used in diagnosing the liver disease caused by α1-antitrypsin deficiency (ATD). Due to its rarity and because it is more frequently encountered as a cause of chronic obstructive pulmonary disease (COPD), ATD is not common for hepatologists to encounter. Discovered in three patients with COPD in 1963 [2], ATD was diagnosed some years later in an infant with liver disease [3]. In 1986, Eriksson et al. [4] described ATD-related adult-onset liver cirrhosis and hepatocellular carcinoma. We now know that the “classical” form of ATD, homozygosity for the α1-antitrypsin Z (ATZ) allele, affects ~1 in 3,000 live births and distinct subgroups of this population are affected by COPD and/or liver disease (reviewed in 5). The underlying genetic defect is a point mutation that leads to protein misfolding with resultant intracellular accumulation of ATZ monomers and polymers accompanied by a marked reduction in ATZ secretion, such that circulating levels are 85–90 % lower than normal. Since α1-antitrypsin (AT) is a serine protease inhibitor, particularly a neutrophil elastase inhibitor, the reduced circulating levels of AT facilitate proteolytic damage of the pulmonary connective tissue matrix by a loss-of-function mechanism. In contrast, liver disease is caused by the proteotoxic effects of misfolded ATZ that accumulates in hepatocytes, a gain-of-toxic function mechanism [5]. Several drugs, some of which are currently approved for other indications, such as carbamazepine, by enhancing the intracellular degradation of misfolded ATZ can reverse liver damage in a mouse model of ATD [6, 7] and thus are being tested clinically. Gene silencing techniques can reverse the liver damage in the ATD mouse model [8]. Furthermore, genomic editing techniques that would potentially correct the underlying genetic defect and therein prevent both liver and lung disease appear to be possible in the near future [9, 10]. …