Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort

Clark, Virginia; Marek, George; Liu, Chen; Collinsworth, Amy; Shuster, Jonathan J.; Kurtz, T.; Nolte, Joanna L.; Brantly, Mark

doi:10.1016/j.jhep.2018.08.005

Cited by 100 publications

(150 citation statements)

References 35 publications

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“…The unique spectrum of epigenetic changes linked to AATD compared with other liver disease drivers further demonstrates that distinct environmental insults leave unique marks on the epigenome and reinforce the importance of our observation that similarities between AATD and obesity‐related liver disease could open insights into AATD biology and treatment. In our original characterization of this clinical cohort, the presence of metabolic syndrome was the strongest predictor of liver fibrosis in AATD . Moreover, the overall prevalence of hepatic steatosis was greater than 40% in our cohort with AATD compared with an expected prevalence of 20%‐30% in the general population .…”

Section: Discussionmentioning

confidence: 70%

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Alpha‐1 Antitrypsin Deficiency Liver Disease, Mutational Homogeneity Modulated by Epigenetic Heterogeneity With Links to Obesity

et al. 2019

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Alpha‐1 antitrypsin deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression, despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in patients with AATD. We examined the contribution of DNA methylation (5‐methylcytosine [5mC]) to AATD liver disease heterogeneity because 5mC responds to environmental and genetic cues and its deregulation is a major driver of liver disease. Using liver biopsies from adults with early‐stage AATD and the ZZ genotype, genome‐wide 5mC patterns were interrogated. We compared DNA methylation among patients with early AATD, and among patients with normal liver, cirrhosis, and hepatocellular carcinoma derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed 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. Further analysis indicated that 5mC changes are localized, with hypermethylation occurring within a background of genome‐wide 5mC loss and with patients with AATD manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observed that CpGs differentially methylated among patients with AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte degeneration and polymer accumulation) and further reveal links to well‐known sex‐specific effects of liver disease progression. Conclusion: Our data reveal molecular epigenetic signatures within this mutationally homogeneous group that point to ways to stratify patients for liver disease risk.

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Section: Discussionmentioning

confidence: 70%

“…A detailed list of clinical parameters for the patients in this study is provided in Supporting Table . A full description of the baseline characteristics of the cohort can be found in Clark et al…”

Section: Resultsmentioning

confidence: 99%

Alpha‐1 Antitrypsin Deficiency Liver Disease, Mutational Homogeneity Modulated by Epigenetic Heterogeneity With Links to Obesity

et al. 2019

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“…This concept of a "toxic gain-of-function" whereby retention of Z within hepatocytes is responsible for liver disease has been recently supported by the evaluation of the relationship between IB (PAS + D) accumulation and fibrosis stages in vivo; at higher fibrosis stages (individuals with ≥F2), the proportion of biopsies with PAS + D inclusions increases. To sum up, accumulation of IB increases as the stage of fibrosis progresses [29]. Furthermore, Z IBs accumulation may precede chronic portal inflammation and the development of liver fibrosis.…”

Section: Z-aat: the Most Common And Severe Variantmentioning

confidence: 93%

“…Furthermore, Z IBs accumulation may precede chronic portal inflammation and the development of liver fibrosis. In clinical practice, the accumulation of these IBs could be a marker for the population at risk of developing fibrosis [29]. Nevertheless, many questions regarding the formation, composition, and heterogeneity in the distribution and size of IB within hepatocytes still remain to be elucidated (Box 1).…”

Section: Z-aat: the Most Common And Severe Variantmentioning

confidence: 99%

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

Karataş

Bouchecareilh

2020

IJMS

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Human cells express large amounts of different proteins continuously that must fold into well-defined structures that need to remain correctly folded and assemble in order to ensure their cellular and biological functions. The integrity of this protein balance/homeostasis, also named proteostasis, is maintained by the proteostasis network (PN). This integrated biological system, which comprises about 2000 proteins (chaperones, folding enzymes, degradation components), control and coordinate protein synthesis folding and localization, conformational maintenance, and degradation. This network is particularly challenged by mutations such as those found in genetic diseases, because of the inability of an altered peptide sequence to properly engage PN components that trigger misfolding and loss of function. Thus, deletions found in the ∆F508 variant of the Cystic Fibrosis (CF) transmembrane regulator (CFTR) triggering CF or missense mutations found in the Z variant of Alpha 1-Antitrypsin deficiency (AATD), leading to lung and liver diseases, can accelerate misfolding and/or generate aggregates. Conversely to CF variants, for which three correctors are already approved (ivacaftor, lumacaftor/ivacaftor, and most recently tezacaftor/ivacaftor), there are limited therapeutic options for AATD. Therefore, a more detailed understanding of the PN components governing AAT variant biogenesis and their manipulation by pharmacological intervention could delay, or even better, avoid the onset of AATD-related pathologies.

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“…We appreciate the interest and comments by Dr. Kumpers 1 et al on our recent work characterizing the clinical and histological findings in patients with severe alpha-1 antitrypsin (AAT) deficiency. 2 To that end, we reviewed how the proposed liver stiffness measurements (LSM) ≥7.1 kPa performed in our cohort. Using that cut-off, the prevalence of clinically significant fibrosis defined as stage ≥2 would be 26%, which is remarkably similar to the 23.6% reported by Hamesch et al 3 in a large study that did not include biopsies.…”

Section: To the Editorsmentioning

confidence: 99%

Reply to: “Assessment of liver phenotype in adults with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype)”

Marek

Brantly

Clark

2019

Journal of Hepatology

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Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort

Cited by 100 publications

References 35 publications

Alpha‐1 Antitrypsin Deficiency Liver Disease, Mutational Homogeneity Modulated by Epigenetic Heterogeneity With Links to Obesity

Alpha‐1 Antitrypsin Deficiency Liver Disease, Mutational Homogeneity Modulated by Epigenetic Heterogeneity With Links to Obesity

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

Reply to: “Assessment of liver phenotype in adults with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype)”

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