Performance of enhanced liver fibrosis test and indirect serum fibrosis markers for exclusion of advanced liver fibrosis in alpha-1 antitrypsin deficiency.

Introduction: Alpha-1 antitrypsin deficiency (AATD) (Pi*ZZ) can cause advanced liver fibrosis and cirrhosis in a subset of patients. Transient elastography (TE) to determine degree of fibrosis has been validated in AATD, but is sometimes unavailable. Serum markers of liver fibrosis have not been tested extensively in AATD.

Severe alpha-1 antitrypsin deficiency is associated with a higher risk of complications after first decompensation than other aetiologies of cirrhosis.

Background & Aims: Alpha-1 antitrypsin deficiency (AATD) causes/predisposes to advanced chronic liver disease. However, the role of the Pi∗ZZ genotype in patients with decompensated cirrhosis is unclear. Thus, we evaluated the impact of the Pi∗ZZ genotype on the disease course after the first hepatic decompensation event.

Clinical Utility of Non-Invasive Tests for Liver Fibrosis in People Living With Alpha-1 Antitrypsin Deficiency.

Severe alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition characterised by low systemic levels of alpha-1 antitrypsin due to its retention in the liver. Consequently, it predisposes individuals to the development of chronic obstructive pulmonary disease and liver cirrhosis. Much progress has been made to non-invasively monitor liver fibrosis and cirrhosis in individuals with other liver diseases, but it remains unclear how to assess liver disease in people with AATD.

Insulin-like Growth Factor-1 Reflects Liver Disease Stage and Improves Prediction of Liver-related Mortality.

Background & Aims: Liver-related mortality represents a growing public health concern, disproportionately affecting younger subjects. Because there are no established tools for early detection of individuals at risk for liver-related death (LRD), we analyzed LRD predictors in the UK Biobank (UKB) data and validated the usefulness of serum insulin-like growth factor-1 (IGF-1).

Methods: The UKB dataset encompassing 325,981 participants, a median follow-up of 13.

Deep Visual Proteomics maps proteotoxicity in a genetic liver disease.

Protein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial health challenges, with their cellular progression still poorly understood. We use spatial proteomics by mass spectrometry and machine learning to map AATD in human liver tissue. Combining Deep Visual Proteomics (DVP) with single-cell analysis, we probe intact patient biopsies to resolve molecular events during hepatocyte stress in pseudotime across fibrosis stages.

Alpha-1 antitrypsin deficiency-associated liver disease: From understudied disorder to the poster child of genetic medicine.

Alpha-1 antitrypsin deficiency (AATD) constitutes an inborn disorder arising due to mutations in alpha-1 antitrypsin (AAT), a secreted protease inhibitor produced primarily in hepatocytes. It leads to diminished serum AAT levels, and this loss-of-function predisposes to chronic obstructive pulmonary disease and lung emphysema. The characteristic Pi*Z mutation results in hepatic Z-AAT accumulation.

Alpha-1 Antitrypsin Inclusions Sequester GRP78 in a Bile Acid-Inducible Manner.

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.

Longitudinal Evaluation of Individuals With Severe Alpha-1 Antitrypsin Deficiency (Pi∗ZZ Genotype).

Background & Aims: Homozygous Pi∗Z mutation in alpha-1 antitrypsin (Pi∗ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only 1 organ, we systematically evaluated an international, multicenter, longitudinal, Pi∗ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints.

Methods: Cohort 1 recruited 737 Pi∗ZZ individuals from 25 different centers without known liver comorbidities who received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM).

Alcohol consumption and liver phenotype of individuals with alpha-1 antitrypsin deficiency.

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).

Association of circulating Z-polymer with adverse clinical outcomes and liver fibrosis in adults with alpha-1 antitrypsin deficiency.

Background: Circulating polymerized mutant Z-alpha-1 antitrypsin (Z-polymer) constitutes a characteristic feature in alpha-1 antitrypsin deficiency (AATD), but there is limited knowledge about its association with adverse clinical outcomes and liver fibrosis. We explored this association using data from a large cohort of adults with AATD.

Methods: A total of 836 (431 PiZZ, 405 PiMZ) adults with AATD and 312 controls (PiMM) from the European Alpha-1 Liver Cohort (2015-2020) were included.

Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

Background & Aims: 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.

Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression.

Background And Aims: Genetic risk factors are major determinants of chronic liver disease (CLD) progression. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M polymorphism and alpha-1 antitrypsin (AAT) E342K variant, termed PiZ, are major modifiers of metabolic CLD. Both variants are known to affect metabolic CLD through increased endoplasmic reticulum stress, but their combined effect on CLD progression remains largely unknown.

Generation of two Alpha-I antitrypsin deficiency patient-derived induced pluripotent stem cell lines ISRM-AATD-iPSC-1 (HHUUKDi011-A) and ISRM-AATD-iPSC-2 (HHUUKDi012-A).

SIX2-positive urine derived renal progenitor cells were isolated from a male and female alpha1-antitrypsin deficiency (AATD) patients both harboring the homozygous PiZZ genotype. The cells were reprogrammed to generate two integration-free induced pluripotent stem cell (iPSC) lines by transfecting episomal-based plasmids expressing OCT4, SOX2, NANOG, c-MYC, KLF4 and LIN28. Pluripotency was confirmed by immunocytochemistry for associated markers and embryoid body-based differentiation into the three germ layers.

Cleaning up alpha-1 antitrypsin deficiency related liver disease.

Purpose Of Review: Alpha-1 antitrypsin deficiency (AATD) is one of the most common genetic disorders arising due to mutations in alpha-1 antitrypsin (AAT) gene affecting primarily the lung and the liver. This review summarizes the pathophysiology and clinical manifestation of different AATD genotypes and discusses the recent therapeutic developments. The focus is on the severe, rare homozygous Pi∗ZZ and the common heterozygous Pi∗MZ genotype.

[From the forest to the ICU and back: an investigative work-up of Amanita phalloides poisoning].

With over 90% of deaths following mushroom ingestion, poisoning with Amatoxin is one of the most dangerous food intoxications. Despite numerous case reports, treatment recommendations are based on a moderate level of evidence due to a lack of randomized controlled trials.We present the case of a 32-year-old patient who presented with acute liver failure after Amanita phalloides (green death cap mushroom) ingestion and whose therapeutic success was significantly influenced by the administration of activated charcoal, silibinin, and N-acetylcysteine as well as the determined research of an external mycologist.

Biomarkers of hepatocellular synthesis in patients with decompensated cirrhosis.

Background And Aim: Since hepatocytes produce majority of serum proteins, patients with cirrhosis display substantial alterations in the serum proteome. The aim of the current study was to characterize these changes and to study the prognostic utility of hepatocellular proteins available in routine clinical testing.

Methods: Sera from 29 healthy controls and 43 patients with cirrhosis were subjected to untargeted proteomic analysis.

Association of Alpha-1 Antitrypsin Pi*Z Allele Frequency and Progressive Liver Fibrosis in Two Chronic Hepatitis C Cohorts.

(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.

Comorbidities in lichen planus by phenome-wide association study in two biobank population cohorts.

Background: Lichen planus (LP) is a relatively frequent mucocutaneous inflammatory disease affecting the skin, skin appendages and mucosae, including oral mucosae, and less frequently the anogenital area, conjunctivae, oesophagus or larynx.

Objectives: To estimate the association of LP, with emphasis on dermatological and gastrointestinal conditions, in two large independent population cohorts.

Materials And Methods: We performed a phenome-wide association study (PheWAS) and examined conditions associated with LP in two unrelated cohorts, i.

Pathophysiology of Chronic Liver Disease Development.

Chronic liver disease is a major public threat and the second leading cause of loss of working life years in Europe [...

The Relationship between Plasma Alpha-1-Antitrypsin Polymers and Lung or Liver Function in ZZ Alpha-1-Antitrypsin-Deficient Patients.

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.

Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder.

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.

Mortality in Patients With Genetic and Environmental Risk of Liver Disease.

Introduction: The increasing liver-related mortality calls for hepatic surveillance programs. To design them, factors selectively increasing liver-related vs overall mortality need to be identified.

Methods: We analyzed mortality data from 467,558 individuals recruited by the community-based UK Biobank.