Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder

Fromme, Malin; Schneider, Carolin V.; Brunetti‐Pierri, Nicola; Strnad, Pavel

doi:10.1016/j.jhep.2021.11.022

Cited by 33 publications

(65 citation statements)

References 126 publications

(141 reference statements)

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“…Last but not least, Rabekova et al took advantage of a large cohort of patients with liver cirrhosis and studied whether genetic variants in the alpha1-antitrypsin gene affect the susceptibility to development of HCC [ 11 ]. In line with previous studies, the heterozygous Pi*MZ genotype was overrepresented in the cirrhotic subjects compared to controls, while the occurrence of the genotype Pi*MS did not differ significantly [ 11 , 12 ]. In contrast, both genotypes were less common in cirrhotics with HCC compared to the ones without [ 11 ].…”

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confidence: 89%

Pathophysiology of Chronic Liver Disease Development

Fromme

Strnad

2022

IJMS

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supporting

confidence: 89%

Pathophysiology of Chronic Liver Disease Development

Fromme

Strnad

2022

IJMS

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“…The AATD-related liver diseases have a wide spectrum of presentations ranging from neonatal to adulthood fibrosis and end-stage cirrhosis requiring transplantation. The current clinical evidence suggests that both organ manifestations are largely independent and triggered by a combination of unique host and environmental factors [24]. This variability in clinical presentation prompted our further search for factors promoting/reflecting AATD-related diseases.…”

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confidence: 99%

The Relationship between Plasma Alpha-1-Antitrypsin Polymers and Lung or Liver Function in ZZ Alpha-1-Antitrypsin-Deficient Patients

et al. 2022

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Alpha-1-Antitrypsin (AAT) is a protein of the SERPINA1 gene. A single amino acid mutation (Lys342Glu) results in an expression of misfolded Z-AAT protein, which has a high propensity to intra- and extra-cellular polymerization. Here, we asked whether levels of circulating Z-AAT polymers are associated with the severity of lung disease, liver disease, or both. We obtained cross sectional data from the Dutch part of the Alpha1 International Registry of 52 ZZ-AAT patients who performed a pulmonary function test and donated a blood sample on the same day. From the Alpha-1 Liver Aachen Registry, we obtained a cohort of 40 ZZ-AAT patients with available data on their liver function. The levels of plasma Z-AAT polymers were determined using a LG96 monoclonal antibody-based sandwich ELISA. In a Dutch cohort, the median plasma level of Z-AAT polymers of patients diagnosed for pulmonary disease was 947.5 µg/mL (733.6–1218 µg/mL (95% CI)), which did not correlate with airflow obstruction or gas transfer value. In the Alpha-1 liver patient cohort, the median polymer level was 1245.9 µg/mL (753–2034 µg/mL (95% CI)), which correlated with plasma gamma-glutamyl transferase (GGT, rs = 0.57, p = 0.001), glutamate dehydrogenase (GLDH, rs = 0.48, p = 0.002) and triglycerides (TG, rs = 0.48, p = 0.0046). A Wilcoxon rank test showed higher Z-AAT polymer values for the liver over the lung group (p < 0.0001). These correlations support a possible link between plasma Z-AAT polymers and the liver function.

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“…Among them, liver stiffness measurement by transient elastography and determination of aspartate aminotransferase to platelet ratio index (APRI) in serum might be particularly suitable to estimate the amount of histological liver fibrosis (64)(65)(66). Regular liver ultrasounds are recommended for individuals with advanced liver fibrosis as a method for HCC surveillance (67).…”

Section: Novel Insights Into the Alpha1-antitrypsin Deficiency-related Liver Diseasementioning

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Liver Fibrosis—From Mechanisms of Injury to Modulation of Disease

et al. 2022

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The Transregional Collaborative Research Center “Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease” (referred to as SFB/TRR57) was funded for 13 years (2009–2021) by the German Research Council (DFG). This consortium was hosted by the Medical Schools of the RWTH Aachen University and Bonn University in Germany. The SFB/TRR57 implemented combined basic and clinical research to achieve detailed knowledge in three selected key questions: (i) What are the relevant mechanisms and signal pathways required for initiating organ fibrosis? (ii) Which immunological mechanisms and molecules contribute to organ fibrosis? and (iii) How can organ fibrosis be modulated, e.g., by interventional strategies including imaging and pharmacological approaches? In this review we will summarize the liver-related key findings of this consortium gained within the last 12 years on these three aspects of liver fibrogenesis. We will highlight the role of cell death and cell cycle pathways as well as nutritional and iron-related mechanisms for liver fibrosis initiation. Moreover, we will define and characterize the major immune cell compartments relevant for liver fibrogenesis, and finally point to potential signaling pathways and pharmacological targets that turned out to be suitable to develop novel approaches for improved therapy and diagnosis of liver fibrosis. In summary, this review will provide a comprehensive overview about the knowledge on liver fibrogenesis and its potential therapy gained by the SFB/TRR57 consortium within the last decade. The kidney-related research results obtained by the same consortium are highlighted in an article published back-to-back in Frontiers in Medicine.

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Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder

Cited by 33 publications

References 126 publications

Pathophysiology of Chronic Liver Disease Development

Pathophysiology of Chronic Liver Disease Development

The Relationship between Plasma Alpha-1-Antitrypsin Polymers and Lung or Liver Function in ZZ Alpha-1-Antitrypsin-Deficient Patients

Liver Fibrosis—From Mechanisms of Injury to Modulation of Disease

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