Current status and perspective on molecular targets and therapeutic intervention strategy in hepatic ischemia-reperfusion injury.

Hepatic ischemia‒reperfusion injury (HIRI) is a common and inevitable complication of hepatic trauma, liver resection, or liver transplantation. It contributes to postoperative organ failure or tissue rejection, eventually affecting patient prognosis and overall survival. The pathological mechanism of HIRI is highly complex and has not yet been fully elucidated. The proposed underlying mechanisms include mitochondrial damage, oxidative stress imbalance, abnormal cell death, immune cell hyperactivation, intracellular inflammatory disorders and other complex events. In addition to serious clinical limitations, available antagonistic drugs and specific treatment regimens are still lacking. Therefore, there is an urgent need to not only clarify the exact etiology of HIRI but also reveal the possible reactions and bottlenecks of existing drugs, helping to reduce morbidity and shorten hospitalizations. We analyzed the possible underlying mechanism of HIRI, discussed various outcomes among different animal models and explored neglected potential therapeutic strategies for HIRI treatment. By thoroughly reviewing and analyzing the literature on HIRI, we gained a comprehensive understanding of the current research status in related fields and identified valuable references for future clinical and scientific investigations.

Histological species differences among chickens, rats, and mice in experimental cholestasis by bile duct ligation.

Cholestasis is a hepatic disease reported in humans, dogs, and chickens and is characterized by various signs. Bile duct ligation (BDL) is a standard model for research in cholestasis in male rats and mice. However, the timing and degree of structural changes in BDL-subjected liver differ in the two animal species. This study focused on chickens as a choice model for cholestasis. Specifically, we aimed to evaluate the features of BDL in hens and compare them with those in rats and mice. Eighteen hens, 19 female ICR mice, and 18 female SD rats were randomly divided into the sham-operated and BDL groups. At 2, 4, and 6 weeks after BDL, and 4 weeks after the sham operation, liver and blood samples were collected and analyzed histologically and biochemically. Histologically, bile duct proliferation in BDL-subjected livers was first observed in the chickens and then the rats and mice, whereas CD44-positive small hepatocytes were observed only in chickens in the BDL group. Biochemically, the mRNA expression of the hepatocyte growth factor was higher in BDL-subjected chickens, while Interleukin 6 expression was higher in the BDL-subjected rats and mice than in animals in the sham group. In addition, farnesoid X receptor mRNA expression was lower in the BDL-subjected chickens than in the sham chickens. The BDL group had significantly higher total bile acid blood concentration than the sham group. In conclusion, the signs of hepatopathy caused by BDL differ among animal species. Furthermore, we propose that compared to BDL-subjected mice and rats, BDL-subjected chickens are a novel cholestasis animal model that demonstrates severe hepatopathy and liver restructuring.

A Case of Metformin-Associated Lactic Acidosis Complicated by Acute Liver Failure, Acute Renal Failure, and Shock.

Metformin is an oral antihyperglycemic agent used for type 2 diabetes mellitus (T2DM) management and is considered to be the first-line treatment for diabetic patients. It works by improving insulin sensitivity, reducing intestinal absorption, and decreasing glucose production in the liver, leading to decreased blood glucose levels. It is generally considered a safe drug; however, it is associated with an uncommon but serious side effect known as metformin-associated lactic acidosis (MALA), a potentially life-threatening condition. Patients with renal failure and liver disease are at high risk of developing MALA; therefore, the medication should be used cautiously in these patients. The diagnosis of MALA requires high suspicion from the physician of this specific entity; otherwise, it may be easily missed. Herein, we report a case of a 63-year-old female with alcoholic liver disease on metformin who was found to have MALA complicated by acute decompensated liver failure, renal failure, and shock.

Immunological crossroads: The intriguing dance between hepatitis C and autoimmune hepatitis.

Delving into the immunological crossroads of liver diseases, this editorial explores the dynamic interplay between hepatitis C virus (HCV) and autoimmune hepatitis (AIH). While HCV primarily manifests as a viral infection impacting the liver, previous studies unveil a captivating connection between HCV and the emergence of AIH. The dance of the immune system in response to HCV appears to set the stage for an intriguing phenomenon-an aberrant autoimmune response leading to the onset of AIH. Evidence suggests a heightened presence of autoimmune markers in individuals with chronic HCV infection, hinting at a potential overlap between viral and autoimmune liver diseases. Navigating the intricate terrain of viral replication, immune response dynamics, and genetic predisposition, this editorial adds a layer of complexity to our understanding of the relationship between HCV and AIH. In this immunological crossroads, we aim to unearth insights into the complex interplay, using a compelling case where AIH and primary sclerosing cholangitis overlapped following HCV treatment with direct-acting antivirals as background.

Unveiling the role of the Hedgehog signaling pathway in chronic liver disease: Therapeutic insights and strategies.

The Hedgehog (Hh) signaling plays a crucial role in adult liver repair by promoting the expansion and differentiation of hepatic progenitor cells into mature hepatocytes and cholangiocytes. Elevated Hh signaling is associated with severe chronic liver diseases, making Hh inhibitors a promising therapeutic option. Sonidegib and vismodegib, both FDA-approved Smoothened (Smo) inhibitors for basal cell carcinoma (BCC), have shown potential for application in chronic liver disorders based on clinical evidence. We highlight the vital role of the Hh pathway in metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and hepatocellular carcinoma (HCC). Moreover, therapeutic strategies targeting the Hh pathway in chronic liver diseases have been discussed, providing a basis for improving disease management and outcomes.

Macrophage Perspectives in Liver Diseases: Programmed Death, Related Biomarkers, and Targeted Therapy.

Macrophages, as important immune cells of the organism, are involved in maintaining intrahepatic microenvironmental homeostasis and can undergo rapid phenotypic changes in the injured or recovering liver. In recent years, the crucial role of macrophage-programmed cell death in the development and regression of liver diseases has become a research hotspot. Moreover, macrophage-targeted therapeutic strategies are emerging in both preclinical and clinical studies. Given the macrophages' vital role in complex organismal environments, there is tremendous academic interest in developing novel therapeutic strategies that target these cells. This review provides an overview of the characteristics and interactions between macrophage polarization, programmed cell death, related biomarkers, and macrophage-targeted therapies. It aims to deepen the understanding of macrophage immunomodulation and molecular mechanisms and to provide a basis for the treatment of macrophage-associated liver diseases.

IL-1 receptor-associated kinase family proteins: An overview of their role in liver disease.

The interleukin-1 receptor-associated kinase (IRAK) family is a group of serine-threonine kinases that regulates various cellular processes via toll-like receptor (TLR)/interleukin-1 receptor (IL1R)-mediated signaling. The IRAK family comprises four members, including IRAK1, IRAK2, IRAK3, and IRAK4, which play an important role in the expression of various inflammatory genes, thereby contributing to the inflammatory response. IRAKs are key proteins in chronic and acute liver diseases, and recent evidence has implicated IRAK family proteins (IRAK1, IRAK3, and IRAK4) in the progression of liver-related disorders, including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis virus infection, acute liver failure, liver ischemia-reperfusion injury, and hepatocellular carcinoma. In this article, we provide a comprehensive review of the role of IRAK family proteins and their associated inflammatory signaling pathways in the pathogenesis of liver diseases. The purpose of this study is to explore whether IRAK family proteins can serve as the main target for the treatment of liver related diseases.

Innate-like T cells in liver disease.

Mammalian innate-like T cells (ILTCs), including mucosal-associated invariant T (MAIT), natural killer T (NKT), and γδ T cells, are abundant tissue-resident lymphocytes that have recently emerged as orchestrators of hepatic inflammation, tissue repair, and immune homeostasis. This review explores the involvement of different ILTC subsets in liver diseases. We explore the mechanisms underlying the pro- and anti-inflammatory effector functions of ILTCs in a context-dependent manner. We highlight latest findings regarding the dynamic interplay between ILTC functional subsets and other immune and parenchymal cells which may inform candidate immunomodulatory strategies to achieve improved clinical outcomes in liver diseases. We present new insights into how distinct gene expression programs in hepatic ILTCs are induced, maintained, and reprogrammed in a context- and disease stage-dependent manner.

The deleterious effects and potential therapeutic strategy of fluorene-9-bisphenol on circadian activity and liver diseases in zebrafish and mice.

Increasing evidence indicates that disturbance of the clock genes, which leads to systemic endocrine perturbation, plays a crucial role in the pathogenesis of metabolic and liver diseases. Fluorene-9-bisphenol (BHPF) is utilized in the manufacturing of plastic materials but its biological effects on liver homeostasis remain unknown. The impacts and involved mechanisms of BHPF on the liver diseases, metabolism, and circadian clock were comprehensively studied by zebrafish and mouse models. The therapeutic effect of melatonin (MT) was also verified. Zebrafish and mouse models with either acute exposure (0.5 and 1 µmol/L, 1-4 days post-fertilization) or chronic oral exposure (0.5 and 50 mg/(kg·2 days), 30 days) were established with various BHPF concentrations. Herein, we identified a crucial role for estrogenic regulation in liver development and circadian locomotor rhythms damaged by BHPF in a zebrafish model. BHPF mice showed chaos in circadian activity through the imbalance of circadian clock component Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-like 1 in the liver and brain. The liver sexual dimorphic alteration along with reduced growth hormone and estrogens played a critical role in damaged glucose metabolism, hepatic inflammation, and fibrosis induced by BHPF. Besides, sleep improvement by exogenous MT alleviated BHPF-related glucose metabolism and liver injury in mice. We proposed the pathogenesis of metabolic and liver disease resulting from BHPF and promising targeted therapy for liver metabolism disorders associated with endocrine perturbation chemicals. These results might play a warning role in the administration of endocrine-disrupting chemicals in everyday life and various industry applications.

Pathogenesis and interaction of neutrophils and extracellular vesicles in noncancer liver diseases.

Liver disease ranks as the eleventh leading cause of mortality, leading to approximately 2 million deaths annually worldwide. Neutrophils are a type of immune cell that are abundant in peripheral blood and play a vital role in innate immunity by quickly reaching the site of liver injury. They exert their influence on liver diseases through autocrine, paracrine, and immunomodulatory mechanisms. Extracellular vesicles, phospholipid bilayer vesicles, transport a variety of substances, such as proteins, nucleic acids, lipids, and pathogenic factors, for intercellular communication. They regulate cell communication and perform their functions by delivering biological information. Current research has revealed the involvement of the interaction between neutrophils and extracellular vesicles in the pathogenesis of liver disease. Moreover, more research has focused on targeting neutrophils as a therapeutic strategy to attenuate disease progression. Therefore, this article summarizes the roles of neutrophils, extracellular vesicles, and their interactions in noncancerous liver diseases.

Exploring the Role of Phenolic Compounds in Chronic Kidney Disease: A Systematic Review.

Chronic kidney disease (CKD) presents a formidable global health concern, affecting one in six adults over 25. This review explores the potential of phenolic compounds in managing CKD and its complications. By examining the existing research, we highlight their diverse biological activities and potential to combat CKD-related issues. We analyze the nutritional benefits, bioavailability, and safety profile of these compounds. While the clinical evidence is promising, preclinical studies offer valuable insights into underlying mechanisms, optimal dosages, and potential side effects. Further research is crucial to validate the therapeutic efficacy of phenolic compounds for CKD. We advocate for continued exploration of their innovative applications in food, pharmaceuticals, and nutraceuticals. This review aims to catalyze the scientific community's efforts to leverage phenolic compounds against CKD-related challenges.

Global mortality of chronic liver diseases attributable to Hepatitis B virus and Hepatitis C virus infections from 1990 to 2019 and projections to 2030.

BACKGROUND: The burden of chronic liver disease (CLD) deaths attributable to the hepatitis B virus (HBV) and hepatitis C virus (HCV) remains unknown. Further research is required to elucidate the extent of this burden in the eventual elimination of these diseases. METHODS: Data on liver cancer, cirrhosis, and other CLD among 204 countries and territories between 1990 and 2019 was extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) published in 2019. The Bayesian age-period-cohort model was used to analyze the temporal trend and predict the disease burden by 2030. RESULTS: The number of HCV-related CLD deaths surpassed that of CLD deaths caused by HBV in 2019 (536833 deaths versus 523003 deaths) and is expected to be maintained until 2030 (689124 deaths versus 628824 deaths). East Asia had the highest burden of chronic HBV and HCV infections during the study period. In 2019, the largest age-standardized death rates (ASDR) of CLD deaths caused by HBV and HCV were mainly observed in Western Sub-Saharan Africa (18.75%) and Eastern Sub-Saharan Africa (16.42%), respectively. South Asia and East Asia are predicted to have the highest number of CLD deaths related to HCV and HBV by 2030. Eastern Europe and South Asia show the largest expected increase in disease burden caused by HCV or HBV between 2019 and 2030. No GBD region is projected to achieve the WHO target of a 65% reduction in mortality from chronic HBV and HCV infections by 2030. CONCLUSIONS: Although the mortality of CLD caused by HBV and HCV decreased in the last three decades (from 1990 to 2019), the number of deaths will continue to increase until 2030. Therefore, governments and international organizations need to strengthen the effectiveness of vaccines, screening, and treatment, especially in potential emerging hotspot regions.

Revolutionizing disease diagnosis and management: Open-access magnetic resonance imaging datasets a challenge for artificial intelligence driven liver iron quantification.

Artificial intelligence (AI), particularly machine learning (ML) and deep learning (DL) techniques, such as convolutional neural networks (CNNs), have emerged as transformative technologies with vast potential in healthcare. Body iron load is usually assessed using slightly invasive blood tests (serum ferritin, serum iron, and serum transferrin). Serum ferritin is widely used to assess body iron and drive medical management; however, it is an acute phase reactant protein offering wrong interpretation in the setting of inflammation and distressed patients. Magnetic resonance imaging is a non-invasive technique that can be used to assess liver iron. The ML and DL algorithms can be used to enhance the detection of minor changes. However, a lack of open-access datasets may delay the advancement of medical research in this field. In this letter, we highlight the importance of standardized datasets for advancing AI and CNNs in medical imaging. Despite the current limitations, embracing AI and CNNs holds promise in revolutionizing disease diagnosis and treatment.

Small intestinal bacterial overgrowth in obese patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease: a cross-sectional study.

Background/aims: The metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity are frequent comorbidities with a high prevalence worldwide. Their pathogenesis are multifactorial, including intestinal dysbiosis. The role of small intestinal bacterial overgrowth (SIBO) in MASLD progression in obese patients remains unknown. We aimed to determine the association between SIBO and the severity of MASLD in obese patients. Methods: An observational and cross-sectional study was conducted in obese patients, diagnosed with or without MASLD by liver biopsy. Metabolic dysfunction-associated steatotic liver (MASL), metabolic dysfunction-associated steatohepatitis without fibrosis (MASH-NF), MASH with fibrosis (MASH-F), or without MASLD (control subjects, CS) were identified by presence of steatosis, portal and lobular inflammation, and fibrosis. SIBO was determined by standardized lactulose breath tests. Results: A total of 59 patients with MASLD, 16 with MASL, 20 with MASH-NF, 23 with MASH-F, and 14 CS were recruited. Higher percentages of SIBO were observed in MASLD patients (44.2%) compared to CS (14.2%; p = 0.0363). Interestingly, MASH-F showed higher percentages of SIBO (65.2%) in comparison to non-fibrotic MASLD (33.3%; p = 0.0165). The presence of SIBO was not correlated with the level of hepatic steatosis in MASLD patients. Conclusions: A positive correlation between MASLD and SIBO in obese patients was principally explained by the presence of liver fibrosis. Our findings suggest a pathogenic role of intestinal dysbiosis in the progression of MASLD. Future research will elucidate the underlying mechanisms of SIBO in MASLD advancement.

Impact of the 2008 economic crisis on the burden of hepatitis B and C diseases in Southern European countries.

BACKGROUND: The economic crisis that began in 2008 has severely affected Southern (Greece, Italy, Portugal, Spain) Western European (SWE) countries of Western Europe (WE) and may have affected ongoing efforts to eliminate viral hepatitis. This study was conducted to investigate the impact of the economic crisis on the burden of HBV and HCV disease. METHODS: Global Burden of Diseases 2019 data were used to analyse the rates of epidemiological metrics of HBV and HCV acute and chronic infections in SWE and WE. Time series modelling was performed to quantify the impact of healthcare expenditure on the time trend of HBV and HCV disease burden in 2000-2019. RESULTS: Declining trends in incidence and prevalence rates of acute HBV (aHBV) and chronic HBV were observed in SWE and WE, with the pace of decline being slower in the post-austerity period (2010-2019) and mortality due to HBV stabilised in SWE. Acute HCV (aHCV) metrics and chronic HCV incidence and mortality showed a stable trend in SWE and WE, whereas the prevalence of chronic HCV showed an oscillating trend, decreasing in WE in 2010-2019 (p < 0.001). Liver cancer due to both hepatitis infections showed a stagnant burden over time. An inverse association was observed between health expenditure and metrics of both acute and chronic HBV and HCV. CONCLUSIONS: Epidemiological metrics for HBV and HCV showed a slower pace of decline in the post-austerity period with better improvement for HBV, a stabilisation of mortality and a stagnant burden for liver cancer due to both hepatitis infections. The economic crisis of 2008 had a negative impact on the burden of hepatitis B and C. Elimination of HBV and HCV by 2030 will be a major challenge in the SWE countries.

Dissecting Acute Drug-Induced Hepatotoxicity and Therapeutic Responses of Steatotic Liver Disease Using Primary Mouse Liver and Blood Cells in a Liver-On-A-Chip Model.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is hallmarked by hepatic steatosis, cell injury, inflammation, and fibrosis. This study elaborates on a multicellular biochip-based liver sinusoid model to mimic MASLD pathomechanisms and investigate the therapeutic effects of drug candidates lanifibranor and resmetirom. Mouse liver primary hepatocytes, hepatic stellate cells, Kupffer cells, and endothelial cells are seeded in a dual-chamber biocompatible liver-on-a-chip (LoC). The LoC is then perfused with circulating immune cells (CICs). Acetaminophen (APAP) and free fatty acids (FFAs) treatment recapitulate acute drug-induced liver injury and MASLD, respectively. As a benchmark for the LoC, multiplex immunofluorescence on livers from APAP-injected and dietary MASLD-induced mice reveals characteristic changes on parenchymal and immune cell populations. APAP exposure induces cell death in the LoC, and increased inflammatory cytokine levels in the circulating perfusate. Under FFA stimulation, lipid accumulation, cellular damage, inflammatory secretome, and fibrogenesis are increased in the LoC, reflecting MASLD. Both injury conditions potentiate CIC migration from the perfusate to the LoC cellular layers. Lanifibranor prevents the onset of inflammation, while resmetirom decreases lipid accumulation in hepatocytes and increases the generation of FFA metabolites in the LoC. This study demonstrates the LoC potential for functional and molecular evaluation of liver disease drug candidates.

Postbiotics Prepared Using Lactobacillus reuteri Ameliorates Ethanol-Induced Liver Injury by Regulating the FXR/SHP/SREBP-1c Axis.

SCOPE: While probiotics-based therapies have exhibited potential in alleviating alcohol-associated liver disease (ALD), the specific role of postbiotics derived from Lactobacillus reuteri (L. reuteri) in ALD remains elusive. This study aims to investigate the impact of postbiotics on ameliorating alcohol-induced hepatic steatosis and the underlying mechanisms. METHODS AND RESULTS: Using network pharmacology, the study elucidates the targets and pathways impacted by postbiotics from L. reuteri, identifying the farnesoid X receptor (FXR) as a promising target for postbiotics against ALD, and lipid metabolism and alcoholism act as crucial pathways associated with postbiotics-targeting ALD. Furthermore, the study conducts histological and biochemical analyses coupled with LC/MS to evaluate the protective effects and mechanisms of postbiotics against ALD. Postbiotics may modulate bile acid metabolism in vivo by regulating FXR signaling, activating the FXR/FGF15 pathway, and influencing the enterohepatic circulation of bile acids (BAs). Subsequently, postbiotics regulate hepatic FXR activated by BAs and modulate the expression of FXR-mediated protein, including short regulatory partner (SHP) and sterol regulatory element binding protein-1c (SREBP-1c), thereby ameliorating hepatic steatosis in mice with ALD. CONCLUSION: Postbiotics effectively alleviate ethanol-induced hepatic steatosis by regulating the FXR/SHP/SREBP-1c axis, as rigorously validated in both in vivo and in vitro.

Harnessing CD8+ T cell dynamics in hepatitis B virus-associated liver diseases: Insights, therapies and future directions.

Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8+ T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8+ T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8+ T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8+ T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8+ T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8+ T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8+ T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.

Assessment of Liver Transplant Eligibility in Chronic Liver Disease Patients: A Cross-Sectional Study From a Tertiary Care Hospital of Pakistan.

INTRODUCTION: The burden of chronic liver disease (CLD) is increasing globally and the ultimate treatment is a liver transplant. As Pakistan is a developing country, liver transplantation is not easily available due to limited resources. This study aims to assess the patients with CLD for liver transplantation and to find the frequency of eligible candidates for liver transplantation. METHODS: A cross-sectional observational study was conducted on patients with CLD from June 2022 to December 2022. Total bilirubin, serum creatinine complete blood count, serum electrolytes, and international normalised ratio (INR) were done. The Model for End-Stage Liver Disease (MELD) score was calculated and the frequency of eligible patients for liver transplant was determined. Data was entered and analyzed using Statistical Package for Social Sciences (SPSS) version 22 (IBM Corp., Armonk, NY, USA). RESULTS: In our study, 149 patients were enrolled with a mean age of 46.81±15.7 years. There were 58.7% male and 41.6% female patients. The mean duration of liver cirrhosis was 18.22±11.7 months. The mean MELD score was 20.71±5.2. The common liver cirrhosis stages were stage II and stage II was found in 32.2% of each. Hepatocellular carcinoma (HCC) was present in 15.4% of patients. There were 25.5% of patients eligible for liver transplants. CONCLUSION: In our study, we found that significant numbers of patients with CLD were eligible for liver transplantation.

[Alpha 1-antitrypsin deficiency]. / Alpha-1-Antitrypsin-Mangel.

Alpha 1­antitrypsin (AAT) deficiency represents a complex genetic disorder and necessitates an interdisciplinary approach in the clinical practice. This article provides an overview of the epidemiology, genetics, symptoms, diagnostics and treatment of AAT deficiency. Knowledge and an in-depth understanding of AAT deficiency are indispensable to improve the early recognition of AAT, to optimize the quality of life of those affected and to enable targeted treatment interventions.