Liver Disease Due to Alpha‐1 Antitrypsin Deficiency: Are We Surprised That It Is More Complex Than We Thought?
Authors: Adrian M. Di Bisceglie, Jeffrey Teckman
Journal: Hepatology (2019)

Potential conflict of interest: Dr. Teckman consults and received grants from Arrowhead, Alnylam, and Dicerna. See Article on Page 51 Alpha‐1 antitrypsin deficiency (AATD) resulting from mutations in the SERPINA1 gene is associated with decreased circulating level of alpha‐1 antitrypsin, and homozygosity for the Z allele is well‐known to result in both lung disease (in the form of emphysema) and liver disease.1 Historically, the liver disease has been described as being different at different times in life. Thus, AATD is a cause of neonatal hepatitis and jaundice,2 has been shown to be associated with a picture of chronic hepatitis, and, finally, is associated with cirrhosis and end‐stage liver disease including hepatocellular carcinoma (HCC).2 These descriptions represent mile markers in the natural history of liver disease associated with AATD. However, there has been very little study on the space in between those markers. For example, what happens to those infants who survive neonatal hepatitis? It appears that the clinical features of acute liver injury initially resolve, but does their liver disease recur in later life? What pathological evolution explains the patients who present with cirrhosis in their fifth or sixth decade of life? And, perhaps most interestingly, why do some patients with AATD not get liver disease at all? It is somewhat surprising that long‐term natural history studies of liver disease in AATD have only recently begun to be carried out, given that the basics of disease pathogenesis have been known for some time. Wang et al.5 take advantage of one such study to look at mechanisms of liver disease. We have come to appreciate that the pathogenesis of liver and lung disease in AATD are very different. Thus, although emphysema develops because of a lack of antitrypsin activity in pulmonary alveoli with resultant damage to those alveoli and the development of emphysema, liver injury has been linked to the accumulation of misfolded alpha‐1 antitrypsin within the endoplasmic reticulum (ER) of hepatocytes. This accumulation appears to result in ER stress, macroautophagy, and other pathways that result in liver cell death. Wang et al. used liver tissue collected from 94 ZZ patients undergoing liver biopsy as part of a natural history study to examine epigenetic heterogeneity—specifically DNA methylation—associated with liver disease. They compared their findings to those in liver tissue from a smaller number of cirrhotic livers associated with AATD and collected in a separate study. They found globally significant genomic hypomethylation in AATD liver‐impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. They also examined their findings in the context of liver disease due to other causes associated with cirrhosis and HCC, by making use of data from The Cancer Genome Atlas and found that many of the genomic features enriched in the AATD groups were also enriched in the obesity/fatty liver–related samples. Although there may be some technical issues in this study that merit discussion related to sample selection and comparisons, these data offer new insights into factors that may account for the heterogeneity in clinical expression of AATD. Thus, there are clearly differences in hepatic DNA methylation patterns in comparing patients with noncirrhotic (mostly mild) liver disease to those with cirrhosis, but is this cause or effect? Is progressive hepatic injury, fibrosis, and remodeling associated with progressive hypomethylation or is it the differential methylation status that leads to liver disease progression? This could only be determined by longitudinal follow‐up of individuals with AATD, with assessment of methylation status along the way. Even within the clinical sample of 94 noncirrhotic liver biopsies, there is considerable heterogeneity. Patients would have had liver biopsies done for different reasons: some for clinical evaluation and others as part of a research project. They range in age from 25 to 71 years at the time of biopsy. Interestingly, not all had periodic acid–Schiff–positive diastase‐resistant globules noted on liver biopsy (5 of 94). Most had mild or minimal hepatic fibrosis, although 35% had F2 or F3 fibrosis. How might hypomethylation be associated with progressive liver injury? Epigenetic changes affect gene activity without altering the sequence of DNA, and can occur at sites throughout the genome. DNA demethylation and histone modifications at gene enhancers and promoters facilitate the unwrapping of DNA from histones, facilitate RNA polymerase activity, and tend to increase gene transcriptional activity. The observation of parallels in methylation patterns between individuals with AATD and those seen in association with cirrhosis and HCC with obesity and fatty liver is interesting, and suggests some commonalities. Again, there is great (as‐yet unexplained) heterogeneity in liver injury and fibrosis among those with diabetes, obesity, or the metabolic syndrome. Clearly these findings have possible implications for therapy of AATD‐related liver disease. Infusion of replacement enzyme is used widely to treat AATD lung disease (with modest or even questionable benefit), but has no effect on AATD liver disease. An intriguing approach has been to try to suppress the intrahepatic production and accumulation of alpha‐1 antitrypsin protein using small interfering RNAs and similar genetic approaches. There is substantial evidence of a dose‐response relationship between accumulation of the Z protein in the cell and hepatocellular injury. Thus, it is interesting that among the 94 clinical samples used for this study, there was a correlation between the amount of stainable alpha‐1 antitrypsin in the liver and the degree of hepatic fibrosis, supporting the idea that suppression of the alpha‐1 antitrypsin protein may provide therapeutic benefit.6 Attempts to use therapies that alter DNA methylation are intriguing to consider, but are likely fraught because of concern about off‐target effects. However, the observation of commonalities with liver disease seen in obesity and fatty liver suggests that treatments effective against the latter might also have some benefit against the former. This could be worth testing at least. Furthermore, this study opens the door to further exploration of factors involved in the pathogenesis of liver disease in AATD. Not only do we need better phenotypic characterization of adults with AATD, to get a better idea of the range of liver pathology that may occur, but we also need longitudinal follow‐up to allow us to test what occurs within the liver over time. Are there other environmental factors that may influence the frequency and rate of progression of liver disease, such as diet, alcohol consumption, coexistent liver diseases, or concomitant medications being used? Certainly, cigarette smoking is known to accelerate the lung disease of AATD: Is there a liver‐equivalent to smoking? It has been very difficult to show a link between excessive alcohol consumption and AATD liver disease. Nonalcoholic fatty liver disease (NAFLD) is an important co‐factor in liver disease progression with viral hepatitis and perhaps even alcohol: Given the findings of this study, should we be advising patients to lose weight? Perhaps we should be doing more liver biopsies early on to determine the presence of NAFLD? We should certainly be exploring other genetic factors associated with AATD liver disease. What about other epigenetic factors in addition to methylation? Is it perhaps possible that a second genetic modification is necessary for liver disease to occur? Potential genetic modifiers of lung disease have been identified and include genetic variations in MMP1, MMP3 and TNF, which encode for matrix metalloproteinases and tumor necrosis factor, respectively1; no similar modifiers of liver disease have yet been identified. Genome‐wide association analysis or other approaches aimed at identifying linkage disequilibrium may be applied very usefully to the study of individuals with a broad spectrum of liver disease associated with AATD. This would mean that we hepatologists will have to go looking for individuals who are homozygous for the ZZ allele rather than having them come to us (when they already have liver disease). Thus, if individuals are identified as having liver disease by virtue of having elevated serum aminotransferases or some other abnormality on screening (perhaps liver elastography), we will miss those with minimal or no liver disease. The gene frequency for the Z allele is about 1 in 50; hence, the disease frequency should be about 1 in 2,500 of the population. We need to find ways to identify these persons and study them to see whether we can prevent the development of end‐stage liver disease in later adulthood.