Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation

Hamesch, Karim; Mandorfer, Mattias; Pereira, Vítor Magno; Moeller, Linda S.; Pons, Mónica; Dolman, Grace; Reichert, Matthias; Schneider, Carolin V.; Woditsch, V; Voss, Jessica; Lindhauer, Cecilia; Fromme, Malin; Spivak, Igor; Güldiken, Nurdan; Zhou, Biaohuan; Arslanow, Anita; Schaefer, Benedikt; Zoller, Heinz; Aigner, Elmar; Reiberger, Thomas; Wetzel, Martin; Siegmund, Britta; Simões, Carolina; Gaspar, Rui; Maia, Luís; Costa, Dalila; Bento-Miranda, Mário; Helden, Josef van; Yagmur, Eray; Bzdok, Danilo; Stolk, Jan; Gleiber, Wolfgang; Knipel, V.; Windisch, Wolfram; Mahadeva, Ravi; Bals, Robert; Koczulla, Rembert; Barrecheguren, Miriam; Miravitlles, Marc; Janciauskiene, Sabina; Stickel, Felix; Lammert, Frank; Liberal, Rodrigo; Genescà, Joan; Griffiths, William J.; Trauner, Michael; Krag, Aleksander; Trautwein, Christian; Strnad, Pavel

doi:10.1053/j.gastro.2019.05.013

Cited by 85 publications

(130 citation statements)

References 61 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…Patients with liver damage almost always have hypoalbuminemia caused by decreased albumin synthesis by the hepatocytes [23]. Data from a large cohort of patients revealed that ZZ AAT carriers have markedly reduced serum triglyceride and VLDL cholesterol concentrations compared to non-carriers [24]. In the model, we not only confirm that differentiated hepatocyte organoids express ALB, SERPINA1, CYP3A4 and APOB, but also demonstrate that organoids from ZZ AAT individuals have lower expression of ALB and APOB in comparison to organoids from MM AAT.…”

Section: Discussionmentioning

confidence: 99%

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

et al. 2019

Self Cite

View full text Add to dashboard Cite

Background and aims Alpha-1 antitrypsin (AAT) is a product of SERPINA1 gene mainly expressed by hepatocytes. Clinically relevant mutations in the SERPINA1 gene, such as Z (Glu342Lys), results in an expression of misfolded AAT protein having high propensity to polymerize, accumulate in hepatocytes and thus to enhance a risk for hepatocyte damage and subsequent liver disease. So far, the relationship between the Z-AAT accumulation and liver cell damage remains not completely understood. We present three-dimensional organoid culture systems, as a novel tool for modeling Z-AAT-related liver diseases. Methods We have established liver organoids from liver biopsies of patients with homozygous (ZZ) and heterozygous (MZ) deficiency and normal (MM) genotypes of AAT. The features of these organoid models were characterized by analyzing AAT protein secretion and intracellular aggregation in MZ and ZZ genotypes as well as SERPINA1 expression in differentiated cultures. Results Transcriptional analysis of differentiated organoid cultures by RNA-Seq showed hepatocyte-specific gene expression profile. Genes, such as ALB, APOB, CYP3A4 and SERPINA1, were validated and confirmed through quantitative-PCR analysis. The organoids from MZ and ZZ cases showed intracellular aggregation and lower secretion of AAT protein, and lower expression of ALB and APOB, as typically seen in hepatocytes from Z-AAT deficiency patients. Furthermore, organoids responded to external stimulus. Treatment with oncostatin M, a well-known inducer of SERPINA1, increased expression of the full-length transcripts (AAT-1C) as well as the short transcript of AAT (AAT-ST1C4). Conclusions Liver organoid model recapitulates the key features of Z-AAT deficiency and provides a useful tool for disease modeling.

show abstract

Section: Discussionmentioning

confidence: 99%

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…The ATS and ERS suggest monitoring liver function annually, acknowledging an evidence‐based testing protocol is yet to be established . A recent large study of adults with AATD caused by the PiZZ mutation showed significant liver fibrosis in 20–36% of individuals on non‐invasive testing and no evidence of a relationship between lung function and liver fibrosis . While increased age, male sex, elevated liver enzymes and low platelet numbers are associated with increased liver fibrosis, the damage in AATD is mostly clinically silent and often without elevated liver enzymes even in the setting of advanced liver disease .…”

Section: Management Of Aatd (Other Than Augmentation Therapy and Surgmentioning

confidence: 99%

“…A recent large study of adults with AATD caused by the PiZZ mutation showed significant liver fibrosis in 20–36% of individuals on non‐invasive testing and no evidence of a relationship between lung function and liver fibrosis . While increased age, male sex, elevated liver enzymes and low platelet numbers are associated with increased liver fibrosis, the damage in AATD is mostly clinically silent and often without elevated liver enzymes even in the setting of advanced liver disease . Therefore, the diagnosis of AATD‐related liver disease may be delayed until the identification of a significant event such as the development of liver cirrhosis or hepatocellular cancer, which are associated with a poor prognosis …”

Section: Management Of Aatd (Other Than Augmentation Therapy and Surgmentioning

confidence: 99%

“…Transient tissue liver elastography, magnetic resonance elastography and ultrasound elastography are increasingly used for non‐invasive assessment of liver fibrosis. These modalities have been shown to have similar accuracy compared to others in screening for the presence of significant liver fibrosis in AATD and to identify patients at higher risk of developing liver complications who may benefit from closer surveillance . In patients with AATD and established cirrhosis, six‐monthly targeted testing for hepatocellular carcinoma with ultrasound examination of the liver together with serum alpha fetoprotein has been recommended …”

Section: Management Of Aatd (Other Than Augmentation Therapy and Surgmentioning

confidence: 99%

“…109 While increased age, male sex, elevated liver enzymes and low platelet numbers are associated with increased liver fibrosis, the damage in AATD is mostly clinically silent and often without elevated liver enzymes even in the setting of advanced liver disease. 109,110 Therefore, the diagnosis of AATD-related liver disease may be delayed until the identification of a significant event such as the development of liver cirrhosis or hepatocellular cancer, which are associated with a poor prognosis. 107 Liver biopsy is the gold standard for staging liver fibrosis but is unsuitable for the screening or follow-up of asymptomatic patients due to the risk of complications, pain and sampling error.…”

Section: Pharmacological Managementmentioning

confidence: 99%

See 2 more Smart Citations

Diagnosis and treatment of lung disease associated with alpha one‐antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*

et al. 2020

View full text Add to dashboard Cite

AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD‐associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD‐related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD‐related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non‐pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.

show abstract

Nonfasted Liver Stiffness Correlates with Liver Disease Parameters and Portal Hypertension in Pediatric Cholestatic Liver Disease

Shneider

Goodrich

et al. 2020

Hepatol. Commun.

View full text Add to dashboard Cite

Elastographic measurement of liver stiffness is of growing importance in the assessment of liver disease. Pediatric experiences with this technique are primarily single center and limited in scope. The Childhood Liver Disease Research Network provided a unique opportunity to assess elastography in a well‐characterized multi‐institutional cohort. Children with biliary atresia (BA), alpha‐1 antitrypsin deficiency (A1ATD), or Alagille syndrome (ALGS) followed in a prospective longitudinal network study were eligible for enrollment in a prospective investigation of transient elastography (FibroScan). Studies were performed in participants who were nonfasted and nonsedated. Liver stiffness measurements (LSMs) were correlated with standard clinical and biochemical parameters of liver disease along with a research definition of clinically evident portal hypertension (CEPH) graded as absent, possible, or definite. Between November 2016 and August 2019, 550 participants with a mean age of 8.8 years were enrolled, 458 of whom had valid LSMs (BA, n = 254; A1ATD, n = 104; ALGS, n = 100). Invalid scans were more common in participants <2 years old. There was a positive correlation between LSM and total bilirubin, international normalized ratio (INR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma‐glutamyl transpeptidase (GGT), GGT to platelet ratio (GPR), pediatric end‐stage liver disease score, AST to platelet ratio index, and spleen size, and a negative correlation with albumin and platelet count in BA, with similar correlations for A1ATD (except AST, ALT, and albumin) and ALGS (except for INR, GGT, GPR, and ALT). Possible or definite CEPH was more common in BA compared to ALGS and A1ATD. LSM was greater in definite versus absent CEPH in all three diseases. Disease‐specific clinical and biochemical characteristics of the different CEPH grades were observed. Conclusion : It is feasible to obtain LSMs in children, especially over the age of 2 years. LSM correlates with liver parameters and portal hypertension, although disease‐specific patterns exist.

show abstract

Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation

Cited by 85 publications

References 61 publications

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

Diagnosis and treatment of lung disease associated with alpha one‐antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*

Nonfasted Liver Stiffness Correlates with Liver Disease Parameters and Portal Hypertension in Pediatric Cholestatic Liver Disease

Contact Info

Product

Resources

About