9 results on '"Fromme, Malin"'
Search Results
2. Alcohol consumption and liver phenotype of individuals with alpha‐1 antitrypsin deficiency.
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Fromme, Malin, Schneider, Carolin V., Guldiken, Nurdan, Amzou, Samira, Luo, Yizhao, Pons, Monica, Genesca, Joan, Miravitlles, Marc, Thorhauge, Katrine H., Mandorfer, Mattias, Waern, Johan, Schneider, Kai Markus, Sperl, Jan, Frankova, Sona, Bartel, Marc, Zimmer, Holger, Zorn, Markus, Krag, Aleksander, Turner, Alice, and Trautwein, Christian more...
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HEPATIC fibrosis , *ALCOHOL drinking , *HEPATOTOXICOLOGY , *CIRRHOSIS of the liver , *CONSORTIA , *ALPHA 1-antitrypsin deficiency - Abstract
Background and Aims: Alpha‐1 antitrypsin deficiency is an inherited disorder caused by alpha‐1 antitrypsin (AAT) mutations. We analysed the association between alcohol intake and liver‐related parameters in individuals with the heterozygous/homozygous Pi*Z AAT variant (Pi*MZ/Pi*ZZ genotype) found in the United Kingdom Biobank and the European Alpha1 liver consortium. Methods: Reported alcohol consumption was evaluated in two cohorts: (i) the community‐based United Kingdom Biobank (17 145 Pi*MZ, 141 Pi*ZZ subjects, and 425 002 non‐carriers [Pi*MM]); and (ii) the European Alpha1 liver consortium (561 Pi*ZZ individuals). Cohort (ii) included measurements of carbohydrate‐deficient transferrin (CDT). Results: In both cohorts, no/low alcohol intake was reported by >80% of individuals, while harmful consumption was rare (~1%). Among Pi*MM and Pi*MZ individuals from cohort (i), moderate alcohol consumption resulted in a <30% increased rate of elevated transaminases and ~50% increase in elevated gamma‐glutamyl transferase values, while harmful alcohol intake led to an at least twofold increase in the abnormal levels. In Pi*ZZ individuals from both cohorts, moderate alcohol consumption had no marked impact on serum transaminase levels. Among Pi*ZZ subjects from cohort (ii) who reported no/low alcohol consumption, those with increased CDT levels more often had signs of advanced liver disease. Conclusions: Pi*MZ/Pi*ZZ genotype does not seem to markedly aggravate the hepatic toxicity of moderate alcohol consumption. CDT values might be helpful to detect alcohol consumption in those with advanced fibrosis. More data are needed to evaluate the impact of harmful alcohol consumption. [ABSTRACT FROM AUTHOR] more...
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- 2024
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Catalog
3. Association of Alpha-1 Antitrypsin Pi*Z Allele Frequency and Progressive Liver Fibrosis in Two Chronic Hepatitis C Cohorts.
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Mücke, Victoria Therese, Fischer, Janett, Mücke, Marcus Maximilian, Teumer, Alexander, Koch, Alexander, Vermehren, Johannes, Fromme, Malin, Zeuzem, Stefan, Trautwein, Christian, Sarrazin, Christoph, Berg, Thomas, Zhou, Biaohuan, and Hamesch, Karim more...
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HEPATIC fibrosis ,CHRONIC hepatitis C ,GENE frequency ,TRYPSIN inhibitors ,ALPHA 1-antitrypsin deficiency ,DISEASE risk factors - Abstract
(1) Background: The inherited alpha-1 antitrypsin (A1AT) deficiency variant 'Pi*Z' emerged as a genetic modifier of chronic liver disease. Controversial data exist on the relevance of heterozygous Pi*Z carriage ('Pi*MZ' genotype) as an additional risk factor in patients with chronic viral hepatitis C to develop progressive liver fibrosis. (2) Methods: Two prospectively recruited cohorts totaling 572 patients with therapy-naïve chronic viral hepatitis C (HCV) were analyzed. The Frankfurt cohort included 337 patients and a second cohort from Leipzig included 235 patients. The stage of liver fibrosis was assessed by liver biopsy, AST-to-platelet ratio index (APRI) score and Fibrosis-4 (FIB-4) score (Frankfurt) as well as liver stiffness measurement (LSM) via transient elastography (Leipzig). All patients were genotyped for the Pi*Z variant (rs28929474) of the SERPINA1 gene. (3) Results: In the Frankfurt cohort, 16/337 (4.7%) patients carried the heterozygous Pi*Z allele while 10/235 (4.3%) in the Leipzig cohort were Pi*Z carriers. In both cohorts, there was no higher proportion of Pi*Z heterozygosity in patients with cirrhosis compared to patients without cirrhosis or patients with cirrhosis vs. no liver fibrosis. Accordingly, Pi*Z frequency was not different in histological or serological stages of liver fibrosis (F0–F4) and showed no clear association with LSM. (4) Conclusions: Evaluation in two representative HCV cohorts does not indicate Pi*Z heterozygosity as a clinically relevant disease modifier in chronic HCV infection. However, validation in even larger cohorts with longitudinal follow-up is warranted. [ABSTRACT FROM AUTHOR] more...
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- 2023
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4. Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder.
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Fromme, Malin, Schneider, Carolin V., Trautwein, Christian, Brunetti-Pierri, Nicola, and Strnad, Pavel
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HEPATIC fibrosis , *TRYPSIN inhibitors , *LIVER diseases , *DISEASE susceptibility , *THERAPEUTICS , *FIBROSIS - Abstract
Alpha-1 antitrypsin deficiency (AATD) arises from mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT) that lead to AAT retention in the endoplasmic reticulum of hepatocytes, causing proteotoxic liver injury and loss-of-function lung disease. The homozygous Pi∗Z mutation (Pi∗ZZ genotype) is responsible for the majority of severe AATD cases and can precipitate both paediatric and adult liver diseases, while the heterozygous Pi∗Z mutation (Pi∗MZ genotype) is an established genetic modifier of liver disease. We review genotype-related hepatic phenotypes/disease predispositions. We also describe the mechanisms and factors promoting the development of liver disease, as well as approaches to evaluate the extent of liver fibrosis. Finally, we discuss emerging diagnostic and therapeutic approaches for the clinical management of this often neglected disorder. [ABSTRACT FROM AUTHOR] more...
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- 2022
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5. The Relationship between Plasma Alpha-1-Antitrypsin Polymers and Lung or Liver Function in ZZ Alpha-1-Antitrypsin-Deficient Patients.
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Sark, Annelot D., Fromme, Malin, Olejnicka, Beata, Welte, Tobias, Strnad, Pavel, Janciauskiene, Sabina, and Stolk, Jan
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LUNGS , *POLYMERS , *GLUTAMATE dehydrogenase , *LIVER , *PULMONARY function tests , *LUNG diseases - Abstract
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. [ABSTRACT FROM AUTHOR] more...
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- 2022
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6. Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).
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Fromme, Malin, Hamesch, Karim, Schneider, Carolin V., Mandorfer, Mattias, Pons, Monica, Thorhauge, Katrine H., Pereira, Vitor, Sperl, Jan, Frankova, Sona, Reichert, Matthias C., Benini, Federica, Burbaum, Barbara, Kleinjans, Moritz, Amzou, Samira, Rademacher, Laura, Bewersdorf, Lisa, Verbeek, Jef, Nevens, Frederik, Genesca, Joan, and Miravitlles, Marc more...
- Abstract
α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P <.001; bilirubin 49% vs 58% upper limit of normal, P =.019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P <.001; liver stiffness measurement 6.5 vs 7.2 kPa, P =.005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease. [ABSTRACT FROM AUTHOR] more...
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- 2024
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7. Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.
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Schneider, Carolin V., Hamesch, Karim, Gross, Annika, Mandorfer, Mattias, Moeller, Linda S., Pereira, Vitor, Pons, Monica, Kuca, Pawel, Reichert, Matthias C., Benini, Federica, Burbaum, Barbara, Voss, Jessica, Gutberlet, Marla, Woditsch, Vivien, Lindhauer, Cecilia, Fromme, Malin, Kümpers, Julia, Bewersdorf, Lisa, Schaefer, Benedikt, and Eslam, Mohammed more...
- Abstract
Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0–11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling. [ABSTRACT FROM AUTHOR] more...
- Published
- 2020
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8. Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in HFE Knockout Mice.
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Guldiken, Nurdan, Hamesch, Karim, Schuller, Shari Malan, Aly, Mahmoud, Lindhauer, Cecilia, Schneider, Carolin V., Fromme, Malin, Trautwein, Christian, and Strnad, Pavel
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KNOCKOUT mice ,TRYPSIN inhibitors ,IRON ,LIVER ,IRON metabolism ,TRANSFERRIN ,FERRITIN - Abstract
The presence of the homozygous 'Pi*Z' variant of alpha-1 antitrypsin (AAT) ('Pi*ZZ' genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM ≥ 7.1 kPa) compared to those without signs of significant liver fibrosis. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development. [ABSTRACT FROM AUTHOR] more...
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- 2019
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9. Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder
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Carolin V. Schneider, Malin Fromme, Pavel Strnad, Christian Trautwein, Nicola Brunetti-Pierri, Fromme, Malin, Schneider, Carolin V, Trautwein, Christian, Brunetti-Pierri, Nicola, and Strnad, Pavel
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Adult ,Liver Cirrhosis ,Heterozygote ,Disease ,medicine.disease_cause ,Liver disease ,alpha 1-Antitrypsin Deficiency ,Genotype ,Medicine ,Humans ,Child ,liver fibrosis ,Liver injury ,Mutation ,Alpha 1-antitrypsin deficiency ,Hepatology ,business.industry ,liver cirrhosi ,Endoplasmic reticulum ,Pi*Z ,Homozygote ,medicine.disease ,Phenotype ,Fibroscan ,alpha 1-Antitrypsin ,Immunology ,SERPINA1 ,business ,Pi*S - Abstract
Alpha-1 antitrypsin deficiency (AATD) arises from mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT) that lead to AAT retention in the endoplasmic reticulum of hepatocytes, causing proteotoxic liver injury and loss-of-function lung disease. The homozygous Pi∗Z mutation (Pi∗ZZ genotype) is responsible for the majority of severe AATD cases and can precipitate both paediatric and adult liver diseases, while the heterozygous Pi∗Z mutation (Pi∗MZ genotype) is an established genetic modifier of liver disease. We review genotype-related hepatic phenotypes/disease predispositions. We also describe the mechanisms and factors promoting the development of liver disease, as well as approaches to evaluate the extent of liver fibrosis. Finally, we discuss emerging diagnostic and therapeutic approaches for the clinical management of this often neglected disorder. more...
- Published
- 2021
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