Virginia C. Clark

Background and Aims: The severe alpha‐1 antitrypsin deficiency (AATD) genotype Pi*ZZ increases the risk of liver disease (AATD‐LD) and lung disease. While non‐invasive tests (NITs) are widely used for fibrosis stage and monitoring of all liver diseases, the consensus for use in AATD‐LD is limited. A Delphi panel study was conducted to address this need.Method: Healthcare providers who managed at least two patients with AATD‐LD in the past two years participated. Two iterative surveys were developed and administered. The second survey clarified the results from the first and provided deeper feedback. As follow‐up, a real‐time consensus‐building exercise focused on survey topics without consensus. Controlled feedback was anonymous.Results: A total of 20 AATD experts (hepatology [n = 9], pulmonology [n = 6], transplant hepatology [n = 3], gastroenterology [n = 1], and hepatology and transplant hepatology [n = 1]) completed the study. A strong consensus was achieved around the use and evaluation of NITs for risk stratification and monitoring. All panelists agreed that vibration‐controlled transient elastography (VCTE) is the preferred NIT for the initial assessment of AATD‐LD owing to its accessibility and reliability. Magnetic resonance elastography and enhanced liver fibrosis tests were also considered valuable. Most (85%) agreed that VCTE < 8 kPa could indicate no or mild fibrosis and VCTE ≥ 8 kPa could indicate clinically significant fibrosis, which may correspond to fibrosis stage ≥ F2 on the METAVIR scale. Most (85%) agreed that VCTE ≥ 13 kPa may indicate cirrhosis.Conclusion: Utilizing the Delphi technique, this study identified a clinically applicable framework for the diagnosis and monitoring of AATD‐LD. A high level of agreement emerged regarding preferred NITs and their usage, risk stratification and monitoring in the context of AATD‐LD management. The results provide a foundation for future efforts into NIT validation and the development of clinical guidelines for AATD‐LD.

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation. In our study of mitochondrial RNA, we identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD. Methods: Utilizing RNA and protein analysis in an in vitro AATD model, we investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver disease while also characterizing our novel, transgenic AATD mouse model. Results: We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT degradation mediated by SIRT3 appeared independent of proteasomal degradation and regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the lipid droplet surface in a direct interaction with Perilipin2, which coats intracellular lipid droplets. SIRT3 overexpression also induced the degradation of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 overexpression induces lipophagy by enhancing the interaction of Perilipin2 with HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids through this process. Conclusions: In this context, SIRT3 activation may eliminate the hepatic toxic gain-of-function associated with the polymerization of ZAAT, providing a rationale for a potential novel therapeutic approach to the treatment of AATD-mediated liver disease. Export

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Deep vein thrombosis (DVT) continues to be a significant source of morbidity for surgical patients. Inferior vena cava (IVC) filter placement is indicated for DVT in patients who have contraindications to anticoagulation or anticoagulation failure. Over the last decade, there is an exponential increase in IVC filter placement with increased complications reported. These include IVC penetration, IVC occlusion, insertion complication and filter migration. We report a rare case of symptomatic duodenal perforation by an IVC filter migration. This case illustrates that even though IVC migration and perforation is a rare complication, it should be recognized as a potential cause for gastrointestinal (GI) symptoms in these patients.

Background: Alpha-1 antitrypsin deficiency (AATD)-mediated liver disease is a toxic “gain-of-function” inflammation in the liver associated with intracellular retention of mutant alpha-1 antitrypsin. The clinical presentation of the disease includes fibrosis, cirrhosis and liver failure. However, the pathogenic mechanism of AATD-mediated liver disease is not well understood. Here, we investigated the role of plasma extracellular vesicles (EVs) in progression of AATD-mediated liver disease. Methods: EVs were isolated from plasma of AATD individuals with liver disease and healthy controls. Their cytokines and miRNA content were examined by multiplex assay and small RNA sequencing. The bioactivity of EVs was assessed by qPCR, western blot analysis and immunofluorescent experiments using human hepatic stellate cells (HSCs) treated with EVs isolated from control or AATD plasma samples. Results: We have found that AATD individuals have a distinct population of EVs with pathological cytokine and miRNA contents. When HSCs were cultured with AATD plasma derived-EVs, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with healthy control plasma EVs. Conclusion: AATD individuals have a distinct population of EVs with abnormal cytokine and miRNA contents and the capacity to activate HSCs and mediate fibrosis. Better understanding of the components which cause liver inflammation and fibrogenesis, leading to further liver injury, has the potential to lead to the development of new treatments or preventive strategies to prevent AATD-mediated liver disease.