Assessment of liver phenotype in adults with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype)

Kümpers, Julia; Fromme, Malin; Schneider, Carolin V.; Trautwein, Christian; Denk, Helmut; Hamesch, Karim; Strnad, Pavel

doi:10.1016/j.jhep.2019.08.011

Cited by 23 publications

(21 citation statements)

References 4 publications

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“…Therefore, it is not surprising that biopsies performed selectively on Pi*ZZ individuals at risk of fibrosis actually confirmed significant liver fibrosis. 1 We agree that an established and validated cut-off (for LSM) would be an important tool in evaluating patients with AAT deficiency. When used to rule in liver disease, an LSM ≥7.1 kPa may be valuable given their cohort contains a population with more advanced disease.…”

Section: To the Editorssupporting

confidence: 55%

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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Section: To the Editorssupporting

confidence: 55%

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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“…A particular strength of our registry cohort was the noninvasive evaluation of liver fibrosis via LSM in all participants. Although LSM and CAP using TE was not validated in Pi*MZ subjects per se, TE was recently validated in Pi*ZZ subjects 5,11,14 and was extensively validated in both the general population as well as various liver disease entities. [15][16][17][18] LSM demonstrated 5-and 9-times increased odds for significant and advanced liver fibrosis in Pi*MZ individuals vs noncarriers, respectively (Supplementary Table 3).…”

Section: Discussionmentioning

confidence: 99%

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers

et al. 2020

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“…TE was performed as described to non-invasively determine the extent of liver fibrosis via liver stiffness measurement (LSM) [7]. Notably, TE is recognized as an established method for liver fibrosis assessment [31,32] and was recently validated in two biopsy-proven cohorts of Pi*ZZ adults [6,33]. For LSM, the cut-off of 7.1 kPa was used as a surrogate for significant liver fibrosis (i.e., fibrosis grade≥2) [7].…”

Section: Methodsmentioning

confidence: 99%

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

Güldiken

Hamesch

Schuller

et al. 2019

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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.

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Assessment of liver phenotype in adults with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype)

Cited by 23 publications

References 4 publications

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

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

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers

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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