Alpha-1 antitrypsin Pi∗Z allele is an independent risk factor for liver transplantation and death in patients with advanced chronic liver disease

Balcar, Lorenz; Scheiner, Bernhard; Urheu, Markus; Weinberger, Patrick; Paternostro, Rafael; Simbrunner, Benedikt; Hartl, Lukas; Jachs, Mathias; Bauer, Dávid; Semmler, Georg; Willheim, Claudia; Pinter, Matthias; Ferenci, Péter; Trauner, Michael; Reiberger, T; Stättermayer, Albert Friedrich; Mandorfer, Mattias

doi:10.1016/j.jhepr.2022.100562

Cited by 6 publications

(8 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The clinical significance of different single nucleotide polymorphisms (PNPLA3, TM6SF2, MBOAT7 and Pi*ZZ genotype), as risk factor for the progression of chronic liver disease has been reported in literature. [44][45][46][47][48][49] Recently, a polymorphic variant of the MHC class I-related chain A (MICA) gene has been related to liver fibrosis progression in patients with chronic hepatitis C, where association with alterations in TGF-β1 and HSC pathways were described. 50 Previously, one study has linked the presence of a single nucleotide polymorphism (PNPLA3-gene, rs738409 and G/G genotype) as a risk factor for hepatic decompensation in patients with both alcoholic and non-alcoholic fatty liver disease, but not in patients with chronic hepatitis C liver disease.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The polymorphic variant of SerpinB3 (SerpinB3‐PD) is associated with faster cirrhosis decompensation

Martini,

Turato,

Cannito

et al. 2023

Aliment Pharmacol Ther

View full text Add to dashboard Cite

SummaryBackgroundSerpinB3 is a cysteine protease inhibitor involved in liver disease progression due to its proinflammatory and profibrogenic properties. The polymorphic variant SerpinB3‐PD (SB3‐PD), presents a substitution in its reactive centre loop, determining the gain of function.AimsTo disclose the clinical characteristics of a cohort of patients with cirrhosis in relation to the presence of SB3‐PD and to assess the effect of this genetic variant on fibrogenic and inflammatory cytokines in vitro.MethodsWe assessed SB3 polymorphism in 90 patients with cirrhosis, prospectively followed up in our referral centre. We used HepG2 and HuH‐7 cells transfected to overexpress either wild‐type SB3 (SB3‐WT) or SB3‐PD to assess their endogenous effect, while LX2 and THP‐1 cells were treated with exogenous SB3‐WT or SB3‐PD proteins.ResultsPatients carrying SB3‐PD had more severe portal hypertension and higher MELD scores, than patients carrying SB3‐WT. In multivariate analysis, SB3‐PD was an independent predictor of cirrhosis complications. Patients with SB3‐PD polymorphism presented with more severe liver fibrosis and inflammatory features. Hepatoma cells overexpressing SB3‐PD showed higher TGF‐β1 expression than controls. The addition of recombinant SB3‐PD induced an up‐regulation of TGF‐β1 in LX2 cells and a more prominent inflammatory profile in THP‐1 cells, compared to the effect of SB3‐WT protein.ConclusionsThe polymorphic variant SB3‐PD is highly effective in determining activation of TGF‐β1 and inflammation in vitro. Patients with cirrhosis who carry SB3‐PD polymorphism may be more prone to develop severe liver disease progression. However, further validation studies are warranted to support the in vivo relevance of this polymorphism.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The polymorphic variant of SerpinB3 (SerpinB3‐PD) is associated with faster cirrhosis decompensation

Martini,

Turato,

Cannito

et al. 2023

Aliment Pharmacol Ther

View full text Add to dashboard Cite

show abstract

“…With regard to the latter, Pi*SZ subjects seem to carry a ~7times increased HCC risk [45], while Pi*MZ individuals do not and might in fact be even protected from HCC [45,56]. This somewhat puzzling observation might be related to the fact that Pi*MZ with liver cirrhosis decompensate/die faster than individuals without AAT variants [57,58]. While the rate of decompensation in This article is protected by copyright.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…45,56 This somewhat puzzling observation might be related to the fact that Pi Ã MZ with liver cirrhosis decompensate/die faster than individuals without AAT variants. 57,58 While the rate of decompensation in other genotypes remains unknown, it is expected to be also accelerated 59 and because of that, AATD patients with cirrhosis should be evaluated for liver transplantation early on. As it is the case in children, liver transplantation confers a good prognosis in adults, particularly when performed in carefully selected subjects without an advanced lung disease.…”

Section: Liver Disease In Adulthoodmentioning

confidence: 99%

Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency

Ruiz

Lacaille²,

Schrader

et al. 2023

Semin Liver Dis

View full text Add to dashboard Cite

Alpha1-antitrypsin (AAT) deficiency (AATD) arises due to inherited variants in SERPINA1, the AAT gene that impair the production or secretion of this hepatocellular protein and lead to a gain-of-function liver proteotoxicity. Homozygous Pi*Z pathogenic variant (Pi*ZZ genotype) is the leading cause of severe AATD. It manifests in 2-10% of carriers as neonatal cholestasis and 20-35% of adults as significant liver fibrosis. Both children and adults may develop an end-stage liver disease requiring liver transplantation. Heterozygous Pi*Z pathogenic variant (Pi*MZ genotype) constitutes an established disease modifier. Our review summarizes the natural history and management of subjects with both pediatric and adult AATD-associated liver disease. Current findings from a phase 2 clinical trial indicate that RNA silencing may constitute a viable therapeutic approach for adult AATD. In conclusion, AATD is an increasingly appreciated pediatric and adult liver disorder that is becoming an attractive target for modern pharmacologic strategies.

show abstract

“…Alpha-1-antitrypsin deficiency-related liver disease (AATLD) is a manifestation of the 'gain of abnormal function' that results from the accumulation of Z-AAT in liver cells, which triggers intracellular injury that may lead to fibrosis, cirrhosis, liver transplant and death. [14][15][16] The Pi*ZZ genotype predisposes patients to advanced liver disease, while the Pi*MZ genotype, that is, heterozygous Pi*Z presence, is primarily disease-modifying, and is associated with increased disease severity and a more progressive course in patients with other liver illnesses. 14,15,17 The Pi*S allele is not associated with an increased risk for advanced chronic liver disease on its own, 12 however, there is an increased risk when the Pi*Z variant (i.e.…”

Section: Pathog Ene S Is Of Alpha-1-antitryps In Deficien C Y-rel Ate...mentioning

confidence: 99%

Review article: New developments in biomarkers and clinical drug development in alpha‐1 antitrypsin deficiency‐related liver disease

Loomba,

Clark,

Teckman

et al. 2024

Aliment Pharmacol Ther

Self Cite

View full text Add to dashboard Cite

SummaryBackgroundAlpha‐1 antitrypsin liver disease (AATLD) occurs in a subset of patients with alpha‐1 antitrypsin deficiency. Risk factors for disease progression and specific pathophysiologic features are not well known and validated non‐invasive assessments for disease severity are lacking. Currently, there are no approved treatments for AATLD.AimsTo outline existing understanding of AATLD and to identify knowledge gaps critical to improving clinical trial design and development of new treatments.MethodsThis report was developed following a multi‐stakeholder forum organised by the Alpha‐1 Antitrypsin Deficiency Related Liver Disease Expert Panel in which experts presented an overview of the available literature on this topic.ResultsAATLD results from a ‘gain of toxic function’ and primarily manifests in those with the homozygous Pi*ZZ genotype. Accumulation of misfolded ‘Z’ AAT protein in liver cells triggers intracellular hepatocyte injury which may ultimately lead to hepatic fibrosis. Male gender, age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome, including obesity and type 2 diabetes mellitus, are known risk factors for adult AATLD. While the gold standard for assessing AATLD disease activity is liver histology, less invasive measures with low intra‐ and inter‐observer variability are needed. Measurement of liver stiffness shows promise; validated thresholds for staging AATLD are in development. Such advances will help patients by enabling risk stratification and personalised surveillance, along with streamlining the development process for novel therapies.ConclusionsThis inaugural forum generated a list of recommendations to address unmet needs in the field of AATLD.

show abstract

Alpha-1 antitrypsin Pi∗Z allele is an independent risk factor for liver transplantation and death in patients with advanced chronic liver disease

Cited by 6 publications

References 26 publications

The polymorphic variant of SerpinB3 (SerpinB3‐PD) is associated with faster cirrhosis decompensation

The polymorphic variant of SerpinB3 (SerpinB3‐PD) is associated with faster cirrhosis decompensation

Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency

Review article: New developments in biomarkers and clinical drug development in alpha‐1 antitrypsin deficiency‐related liver disease

Contact Info

Product

Resources

About