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Background and Aims: The homozygous PiZ mutation (PIZZ genotype) constitutes the predominant cause of severe alpha‐1 antitrypsin (AAT) deficiency and leads to liver disease via hepatocellular AAT aggregation. We systematically analysed the composition of AAT aggregates and studied the impact of bile acids. Methods: AAT inclusions were isolated from livers of PiZ overexpressing mice and PIZZ humans via fluorescence‐activated and immunomagnetic sorting (FACS/MACS), while insoluble proteins were obtained via Triton‐X extraction. Inclusion composition was evaluated through mass‐spectrometry (MS), immunoblotting and immunostaining. Hepatocytes with versus without AAT aggregates were obtained via microdissection. Serum bile acids were assessed in 57 PIZZ subjects and 19 controls. Mice were administered 2% cholic acid (CA)–supplemented chow for 7 days. Results: MS identified the key endoplasmic reticulum chaperone 78 kDa glucose‐regulated protein (GRP78) in FACS/MACS pulldowns. GRP78 was also enriched in insoluble fractions from PiZ mice versus wild types and detected in insoluble fractions/MACS isolates from PIZZ liver explants. In cultured cells/primary hepatocytes, PiZ overexpression was associated with increased GRP78 mRNA/protein levels. In human livers, hepatocytes with AAT aggregates had higher GRP78 levels than hepatocytes without. PIZZ subjects displayed higher serum bile acid levels than controls and the highest levels were seen in individuals with liver injury/fibrosis. In PiZ mice, CA‐mediated bile acid challenge resulted in increased liver injury and translocation of GRP78 into the aggregates. Conclusions: Our results demonstrate that GRP78 is sequestered within AAT inclusions. Bile acid accumulation, as seen in PIZZ subjects with liver disease, may promote GRP78 segregation and thereby augment liver damage. Trial Registration: NCT02929940 [ABSTRACT FROM AUTHOR]

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]

The article discusses a study on the association between Alpha-1 antitrypsin deficiency (AATD) and increased risks of skin cancer, leukemia, and hepatic cancer. The study analyzed data from the UK Biobank, focusing on individuals with different AATD genotypes. Results showed an increased risk of leukemia and skin cancer in individuals with specific AATD genotypes, providing insights into the association between AATD and various cancers. The study highlights the importance of considering genotype-specific risks and the underdiagnosis of AATD in real life. [Extracted from the article]

Summary: Background: Coeliac disease arises in genetically susceptible individuals, in particular in carriers of HLA‐DQ2/DQ8 risk alleles and is associated with various comorbidities. Coeliac disease may confer an increased mortality, but the data are conflicting. Aims: We aimed to characterize mortality and morbidity in patients with coeliac disease with a special focus on the role of the number of HLA risk alleles. Methods: We studied coeliac disease‐associated morbidity and mortality in ~500 000 participants of the UK Biobank including 2482 individuals with the diagnosis of coeliac disease. We used an unbiased, multivariable Phenome‐Wide Association Study (PheWAS) method to uncover the coeliac disease‐associated disorders. The tag SNP approach was used to divide the coeliac disease subjects into HLA‐DQ2/DQ8‐based risk categories. Results: We found 225 ICD‐10 codes significantly associated with coeliac disease. During the median follow‐up of 10.7 years, coeliac disease individuals (n = 2482) had higher overall mortality (HR 1.6 [95% CI, 1.4‐1.8]) than controls and both an increased occurrence of and an increased mortality from cancer, respiratory and cardiovascular diseases (HR 1.4‐1.6). Coeliac disease individuals with 2 HLA‐DQ2/8 risk alleles had a similar overall mortality as coeliac disease participants with 0‐1 HLA‐DQ2/8 alleles, but were more likely to die from lymphoproliferative diseases (HR 7.6 [95% CI, 1.01‐57.25]). Conclusions: Our data suggest that the increased mortality from lymphoproliferative diseases is restricted to those coeliac patients with 2 HLADQ2/8 alleles and that a combination of coeliac disease and HLADQ2/8 alleles is needed to increase the susceptibility. Once confirmed, closer monitoring may be warranted in this high‐risk subpopulation. [ABSTRACT FROM AUTHOR]

See Article on Page 1136 [ABSTRACT FROM AUTHOR]