Alpha-1 antitrypsin deficiency (A1ATD) is an inherited metabolic disorder caused by a mutation (ZZ) in the SERPINA1 gene. Carriers are predisposed to liver and lung pathology. The severity of A1ATD-associated liver disease is highly variable, necessitating further characterisation. This study aims to investigate the risk and extent of liver disease and the prevalence of liver transplantation in ZZ A1ATD patients. Several established databases, including Ovid, EBSCO, PubMed, and Cochrane Library, were searched from inception to May 12, 2024. Data were pooled using a random effects model, and study weight was calculated using the inverse variance method. Crude odds ratios (cOR) were calculated using participants with the MM genotype as the comparator. The study was registered in PROSPERO (CRD42022335666). Of the 4420 studies identified, 45 studies and 8638 A1ATD patients (38.8% female) were included. ZZ A1ATD patients demonstrate an increased risk of liver diseases compared to controls, including steatosis (crude odds ratio (cOR): 1.52 [95% CI: 1.21, 1.91]), fibrosis (cOR: 9.85 [95% CI: 5.70, 17.03]), cirrhosis (cOR: 10.43 [95% CI: 5.51, 19.73]), and liver cancers (cOR: 14.12 [95% CI: 6.50, 30.66]). The prevalence of liver transplantation is considerable, with rates reaching 5% [95% CI: 0.00, 12.34]. Our findings confirm the substantial burden of liver disease in ZZ A1ATD patients, including subclinical manifestations such as steatosis and fibrosis that may remain undetected. Given the lack of approved treatments for A1ATD-associated liver disease, prioritising the development of novel therapies to stop or reverse liver disease is essential.

Alpha-1 antitrypsin deficiency (AATD) can manifest at any age, including the perinatal period. Its manifestations include obstructive lung disease, which can be severe and for which current therapies are of limited benefit. We sought to determine whether the transamniotic route could be a viable alternative for administering AAT mRNA to the fetus. Twelve pregnant dams underwent volume-matched intra-amniotic injections in all their fetuses (n = 139) of either a suspension of human AAT (hAAT) mRNA encapsulated by a synthetic cationic polymer-based composite, lipopolyplex (mRNA group; n = 99) or of lipopolyplex free of mRNA (controls; n = 40), on gestational day 17 (E17; term = E21). Fetal lung and liver samples were procured daily thereafter until term to screen for hAAT by ELISA. Liver function panels were performed at term. Statistical analysis included median regression (p < 0.05). Fetal survival was 79% (110/139), significantly higher in the mRNA group (p = 0.012). Controlled by mRNA-free injections, hAAT was found in the fetal lungs at all time points (p = 0.005 to < 0.001) but in the liver only at E20, suggesting interspecies homology manifesting at that site. The term liver function panels were comparable between groups. Encapsulated exogenous mRNA encoding for human alpha-1 antitrypsin protein can be incorporated and translated by fetal lung cells following simple intra-amniotic injection in a healthy rat model. Fetal hepatic incorporation and translation remain to be determined in a model with minimal to no human homology. Transamniotic mRNA delivery could become a novel strategy for the perinatal management of alpha-1 antitrypsin deficiency.

Although several SERPINA1 genetic variants have been reported for their pathogenicity to induce liver disorders through phenotype-driven approaches, data regarding genotype-driven approaches of the SERPINA1 locus remain unavailable. This study aimed to characterize the clinical and liver biological profiles of patients harboring nonbenign SERPINA1 variants.

We conducted a retrospective, exome-based genotype-first reverse phenotyping study using structured electronic health record data from consecutive patients from January 1, 2015, to January 31, 2022. Statistical associations were assessed using frequentist and Bayesian models, with validation in the UK Biobank cohort.

Among 1377 patients analyzed, 15 SERPINA1 variants classified as nonbenign were identified in 217 (15.7%) patients. Data were available for 126 patients (median age, 41.5 years; 52.4% male). Liver disease, hyperferritinemia, and pulmonary emphysema were observed in 32.5% (41/126), 23% (29/126), and 5.6% (7/126) of the patients, respectively. The median follow-up duration was 1.3 years and encompassed 1085 biological observations. We confirmed associations with well-documented variants of SERPINA1 (p.Glu366Lys, p.Pro393Ser, p.Ala308Ser, p.Glu288Val, and p.Phe76del). We identified three novel genetic associations with liver markers: c.*10G > A, c.1065 + 10C > T, and p.Arg63Cys. The UK Biobank data confirmed significant gene- and variant-level associations, notably for the variants identified in our study, which ranked in the top decile of statistical associations.

This study supports the utility of a genotype-first approach in characterizing hepatic manifestations of nonbenign SERPINA1 variants. The findings highlight novel genotype-biomarker associations and suggest a role for SERPINA1 genetic testing in patients with unexplained liver abnormalities.

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. In its homozygous form (Pi*ZZ genotype), it is responsible for the majority of severe AATD cases and can cause both pediatric and adult liver disease, while the heterozygous form (Pi*MZ) is considered a disease modifier that becomes apparent primarily in the presence of other comorbidities or risk factors. In the current review, we collate conditions associated with AATD, introduce typical AAT variants, and discuss our understanding of disease pathogenesis. We present both cross-sectional and longitudinal data informing about the natural disease history and noninvasive tools that can be used for disease stratification as well as a basis for disease monitoring. Given that AATD-associated liver disease is highly heterogeneous, we discuss the risk factors affecting disease progression. While the loss-of-function lung disease is treated by weekly intravenous administration of purified AAT, recombinant modified AAT and oral protease inhibitors are currently in clinical trials. Among the liver candidates, small interfering RNA fazirsiran efficiently suppresses AAT production and is currently in phase 3 clinical trial, while several other genetic approaches, such as RNA editing, are at earlier stages. In summary, AATD represents a systemic disorder increasingly seen in the hepatologic routine and requiring thorough interdisciplinary care, since the currently ongoing clinical trials often address only one of the organs it affects.

Primary liver cancers (PLCs) remain a major challenge to global health and an escalating threat to human life, with a growing incidence worldwide. PLCs are composed of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and mixed HCC-CCA, accounting for 85 %, 10 %, and 5 % of cases, respectively. Among the numerous identified risk factors associated with liver cancers, Alpha 1-AntiTrypsin Deficiency (AATD) genetic disease emerges as an intriguing one. AATD-related liver disease may lead to chronic hepatitis, cirrhosis, and PLCs in adulthood. Although our knowledge about the natural history of AATD-liver disease has improved recently, liver cancers associated with AATD remain poorly understood and explored, while this specific population is at a 20 to 50 times higher risk of developing PLC. Thus, we review here current knowledge about AATD-associated PLCs, describing the impact of AATD genotypes on their occurrence. We also discuss emerging hypotheses regarding the AATD PiZZ genotype-related hepatic carcinogenesis process. Finally, we perform an updated analysis of the United Kingdom Biobank database that highlights and confirms AATD PiZZ genotype as an important HCC risk factor.

To elicit the signs and/or symptoms, and impacts on daily living experienced by patients with alpha-1 antitrypsin deficiency-associated liver disease (AATD-LD).

A preliminary "concept list" of signs and/or symptoms, and impacts was developed from a targeted literature review, patient blog posts, and clinician interviews. Subsequently, one-to-one concept elicitation interviews involving English-speaking, US adults with AATD-LD and a protease inhibitor (Pi) ZZ or MZ genotype were conducted by trained interviewers following a central Institutional Review Board-approved discussion guide. An AATD-LD conceptual model was developed based on these findings. Concepts were "most salient" if reported by ≥ 8 patients with a mean bothersomeness/disturbance rating of ≥ 5, or "highly salient" if reported by > 5- < 8 patients with a mean bothersomeness/disturbance rating of ≥ 5 (scale: 0-10, 0: not at all bothersome/disturbing; 10: extremely bothersome/disturbing).

Fifteen patients were interviewed (median [range] age: 57 [28-78] years; Pi*ZZ, n = 12; Pi*MZ, n = 3). Of 41 signs and/or symptoms, the most salient were fatigue/tiredness, respiratory infections, shortness of breath, confusion/difficulty concentrating, and edema. Highly salient signs and/or symptoms were abdominal swelling, acid reflux, sleep disturbance, vomiting, abdominal pain/tenderness, itchiness, and back pain. Of 16 impacts, the most salient were on work and employment, leisure activities, and relationships. Impacts on mobility were highly salient.

Several concepts were frequently reported as moderately/highly bothersome/disturbing. Further investigation of the experience of patients with AATD-LD in a large, diverse population across all fibrosis stages and genotypes is warranted. Clinical outcome assessments that capture salient concepts are needed.

Metabolic dysfunction-associated steatohepatitis (MASH) is associated with the activation of Kupffer cells (KCs) and hepatic stellate cells, at which point a metabolically stressed hepatocyte becomes integral to the progression of the disease. We observed a significant reduction in the level of alpha-1-antitrypsin (A1AT), a hepatocyte-derived secreted factor, in both patients with MASH and mice fed a fast-food diet (FFD). KC-mediated hepatic inflammation, most notably IL-1β, led to the transcriptional inhibition of A1AT by HNF4α. In quintuple Serpina1a-e knockout mice, ablation of A1AT worsened MASH through increased activity of proteinase 3 (PR3), a proinflammatory protease produced by F4/80hi/CD11blow/TIM4-/CCR2+ monocyte-derived KCs (MoKCs). Conversely, A1AT restoration or PR3 inhibition mitigated MASH progression. A PR3-bound cytokine array identified IL-32 as a key factor associated with MASH. Combining IL-32 with SERPINA1, the gene encoding A1AT, synergistically predicted patients at risk of MASH through univariate logistic regression analysis. Furthermore, in vivo overexpression of IL-32γ alleviated MASH induced by FFD. However, additional knockout of A1AT increased PR3 activity, consequently abolishing the anti-MASH effects of IL-32γ. Blocking PR3-mediated IL-32γ cleavage via the V104A mutation sustained its protective actions, while the PR3-cleaved C-terminal fragment activated KCs. Additionally, after cleavage, the antifibrogenic effect of IL-32γ is lost, resulting in a failure to prevent the activation of hepatic stellate cells. This study highlights the critical role of hepatocyte-derived A1AT in the PR3/IL-32γ axis during MASH development. Strategies to correct A1AT dysregulation, such as A1AT supplementation or PR3 inhibition with sivelestat, may offer protection against the development and progression of MASH and fibrosis. Elevated hepatic IL-1β levels in MASH lead to the downregulation of A1AT via the transcription factor HNF4α, resulting in increased recruitment of proinflammatory MoKCs and heightened PR3 activity. PR3 cleaves IL-32γ, transforming it from an anti-inflammatory and antifibrogenic cytokine into a potent activator of KCs and failing to prevent HSC activation. This cascade amplifies liver inflammation and fibrosis, suggesting that targeting the A1AT/PR3/IL-32γ axis could be a strategy for treating MASH.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is a monogenic disease caused by misfolding of AAT variants resulting in gain-of-toxic aggregation in the liver and loss of monomer activity in the lung leading to chronic obstructive pulmonary disease (COPD). Using high-throughput screening, we discovered a bioactive natural product, phenethyl isothiocyanate (PEITC), highly enriched in cruciferous vegetables, including watercress and broccoli, which improves the level of monomer secretion and neutrophil elastase (NE) inhibitory activity of AAT-Z through the endoplasmic reticulum (ER) redox sensor protein disulfide isomerase (PDI) A4 (PDIA4). The intracellular polymer burden of AAT-Z can be managed by combination treatment of PEITC and an autophagy activator. Using Gaussian process (GP)-based spatial covariance (SCV) (GP-SCV) machine learning to map on a residue-by-residue basis at atomic resolution all variants in the worldwide AATD clinical population, we reveal a global rescue of monomer secretion and NE inhibitory activity for most variants triggering disease. We present a proof of concept that GP-SCV mapping of restoration of AAT variant function serves as a standard model to discover natural products such as the anti-oxidant PEITC that could potentially impact the redox/inflammatory environment of the ER to provide a nutraceutical approach to help minimize disease in AATD patients.

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.

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.

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.

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.

NCT02929940.

Alpha-1 antitrypsin deficiency (AATD) is a relatively rare genetic disorder, inherited in an autosomal codominant manner, that results in reduced serum AAT concentrations, with a consequent reduction in antielastase activity in the lungs, as well as an increased risk of diseases such as pulmonary emphysema, liver cirrhosis, and necrotizing panniculitis. It results from different mutations in the SERPINA1 gene, leading to changes in the AAT glycoprotein, which can alter its concentration, conformation, and function. Unfortunately, underdiagnosis is quite common; it is possible that only 10% of cases are diagnosed. The most common deficiency is in the Z variant, and it is estimated that more than 3 million people worldwide have combinations of alleles associated with severe AATD. Serum AAT concentrations should be determined, and allelic variants should be identified by phenotyping or genotyping. Monitoring lung function, especially through spirometry, is essential, because it provides information on the progression of the disease. Although pulmonary densitometry appears to be the most sensitive measure of emphysema progression, it should not be used in routine clinical practice to monitor patients. In general, the treatment is similar to that indicated for patients with COPD not caused by AATD. Exogenous administration of purified human serum-derived AAT is the only specific treatment approved for AATD in nonsmoking patients with severe deficiency (serum AAT concentration of < 57 mg/dL or < 11 µM), with evidence of functional loss above the physiological level.

Alpha-1 antitrypsin deficiency (AATD) is a codominant autosomal hereditary condition that predisposes patients to the development of lung and/or liver disease, and Pi*Z allele is the most clinically relevant mutation.

To evaluate the impact of clinical parameters and AATD phenotypes, particularly the Pi*Z allele, in liver fibrosis.

Cross-sectional cohort study including consecutive patients with AATD followed in Pulmonology or Hepatology consultation.

Included 69 patients, 49.3% had Pi*MZ phenotype and 10.1% Pi*ZZ. An age ≥ 55 years, age at diagnosis ≥ 41 years and AAT at diagnosis < 77 mg/dL predicted a nonalcoholic fatty liver disease fibrosis score (NFS) not excluding advanced fibrosis [area under the curve (AUC) = 0.840, P < 0.001; AUC = 0.836, P < 0.001; AUC = 0.681, P = 0.025]. An age ≥ 50 years and age at diagnosis ≥ 41 years predicted a fibrosis-4 index of moderate to advanced fibrosis (AUC = 0.831, P < 0.001; AUC = 0.795, P < 0.001). Patients with hypertension, type 2 diabetes mellitus (DM), dyslipidaemia, metabolic syndrome, and regular alcohol consumption were more likely to have a NFS not excluding advanced fibrosis (P < 0.001, P = 0.002, P = 0.008, P < 0.001, P = 0.033). Patients with at least one Pi*Z allele and type 2 DM were 8 times more likely to have liver stiffness measurement ≥ 7.1 kPa (P = 0.040).

Risk factors for liver disease in AATD included an age ≥ 50 years, age at diagnosis ≥ 41 years, metabolic risk factors, regular alcohol consumption, at least one Pi*Z allele, and AAT value at diagnosis < 77 mg/dL. We created an algorithm for liver disease screening in AATD patients to use in primary care, selecting those to be referred to Hepatology consultation.

The remarkable impact of RNA nanomedicine during the COVID-19 pandemic has demonstrated the expansive therapeutic potential of this field in diverse disease contexts. In recent years, RNA nanomedicine targeting the liver has been paradigm-shifting in the management of metabolic diseases such as hyperoxaluria and amyloidosis. RNA nanomedicine has significant potential in the management of liver diseases, where optimal management would benefit from targeted delivery, doses titrated to liver metabolism, and personalized therapy based on the specific site of interest. In this review, we discuss in-depth the different types of RNA and nanocarriers used for liver targeting along with their specific applications in metabolic dysfunction-associated steatotic liver disease, liver fibrosis, and liver cancers. We further highlight the strategies for cell-specific delivery and future perspectives in this field of research with the emergence of small activating RNA, circular RNA, and RNA base editing approaches.

Genetic cholestatic liver diseases are caused by (often rare) mutations in a multitude of different genes. While these diseases differ in pathobiology, clinical presentation and prognosis, they do have several commonalities due to their cholestatic nature. These Clinical Practice Guidelines (CPGs) offer a general approach to genetic testing and management of cholestatic pruritus, while exploring diagnostic and treatment approaches for a subset of genetic cholestatic liver diseases in depth. An expert panel appointed by the European Association for the Study of the Liver has created recommendations regarding diagnosis and treatment, based on the best evidence currently available in the fields of paediatric and adult hepatology, as well as genetics. The management of these diseases generally takes place in a tertiary referral centre, in order to provide up-to-date approaches and expertise. These CPGs are intended to support hepatologists (for paediatric and adult patients), residents and other healthcare professionals involved in the management of these patients with concrete recommendations based on currently available evidence or, if not available, on expert opinion.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by specific variants in the SERPINA1 gene, which encodes AAT. The most common disease-associated SERPINA1 variants are Pi∗S and Pi∗Z alleles, which cause moderate and severe AATD, respectively. Recent studies have reported the presence of a possible regulator of SERPINA gene cluster expression (LOC126862032), which is suggested to act as a BRD4-Independent Enhancer (SERPINA-BIE). This study is aimed at characterizing the SERPINA-BIE locus and assessing possible associations with SERPINA1 AATD-related alleles. For this purpose, SERPINA-BIE was PCR genotyped from 917 samples, including 452 asthmatic patients, and 465 newborns. Nine SERPINA-BIE alleles were sequenced, revealing a specific combination of 56-bp sequence types, and each SERPINA-BIE allele has a unique total number of CpG sites. Statistical analyses revealed an association between the Pi∗Z allele of the SERPINA1 gene and the SERPINA-BIE allele 13 (p value = 5.51 × 10-10), as well as between Pi∗S and SERPINA-BIE allele 14 (p value = 8.95 × 10-15). However, AAT levels were not associated with SERPINA-BIE alleles when models were corrected by SERPINA1 genotypes. This study could contribute to a better understanding of the regulation of the SERPINA1 gene expression, and its role in AATD.

This study aimed to analyse the clinical course of 45 children with severe alpha-1-antitrypsin deficiency (AATD) registered in our clinic to detect possible predictors of poor outcomes.

The clinical and biological data of 45 patients with homozygous or compound heterozygous AATD were analysed. The data were collected retrospectively going back to 2005 and prospectively from May 2020 until October 2021. It was based on questionnaires, laboratory values, sonography, and biopsy findings. Liver disease was classified into four grades depending on the grade of liver disease: mild or no liver disease, moderate disease, severe disease, and liver transplantation.

Thirty-nine patients (86.7%) had a Pi*ZZ and five (11.1%) a Pi*SZ genotype. One patient showed a new, not-yet-described compound heterozygous genotype (Pi*Z + Asp95Asn). A total of 66.7% of the cohort showed mild or no liver disease, 20% moderate, and 13.3% severe. AATD was diagnosed in most cases because of liver abnormalities, such as the elevation of transaminases (42.2%). A total of 29.4% of the patients with neonatal icterus prolongatus developed severe liver disease, and 25.7% were born small for their gestational age (SGA). Diseases of the atopic type were reported in 47.4% of the cases.

The presence of neonatal icterus prolongatus in the first weeks of life was significantly more likely in severe courses of liver disease (r = 0.371, p = 0.012). A tendency toward atopic comorbidity in AAT-deficient children needs to be further evaluated.

Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition caused by decreased plasma and tissue levels of alpha-1 antitrypsin (AAT) that can lead to serious lung and liver disease in children and adults. AATD patients face challenges such as under diagnosis, clinical variability, and limited treatment options for liver disease. Early detection and biomarkers for predicting outcomes are needed to improve patient outcome. Currently, the only approved pharmacological therapy is augmentation therapy, which can delay the progression of emphysema. However, alternative strategies such as gene therapy, induced pluripotent stem cells, and prevention of AAT polymerization inside hepatocytes are being investigated. This review aims to summarize and update current knowledge on AATD, identify areas of controversy, and formulate questions for further research.

Improved outcomes of liver disease in childhood and young adulthood have resulted in an increasing number of young adults (YA) entering adult liver services. The adult hepatologist therefore requires a working knowledge in diseases that arise almost exclusively in children and their complications in adulthood.

To provide adult hepatologists with succinct guidelines on aspects of transitional care in YA relevant to key disease aetiologies encountered in clinical practice.

A systematic literature search was undertaken using the Pubmed, Medline, Web of Knowledge and Cochrane database from 1980 to 2023. MeSH search terms relating to liver diseases ('cholestatic liver diseases', 'biliary atresia', 'metabolic', 'paediatric liver diseases', 'autoimmune liver diseases'), transition to adult care ('transition services', 'young adult services') and adolescent care were used. The quality of evidence and the grading of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

These guidelines deal with the transition of YA and address key aetiologies for the adult hepatologist under the following headings: (1) Models and provision of care; (2) screening and management of mental health disorders; (3) aetiologies; (4) timing and role of liver transplantation; and (5) sexual health and fertility.

These are the first nationally developed guidelines on the transition and management of childhood liver diseases in adulthood. They provide a framework upon which to base clinical care, which we envisage will lead to improved outcomes for YA with chronic liver disease.

The longitudinal health status of Danish children with alpha-1 antitrypsin deficiency had never previously been characterised. This study aimed to assess the changes in growth, lung and liver function through childhood in these children.

Danish children diagnosed between 2005 and 2020 with pathogenic variants in the Serpin family A member 1 gene were included. Retrospective data on growth, lung and liver parameters were obtained from local databases. Anthropometric Z-scores and composite liver scores were computed. Growth and blood results were analysed using robust linear mixed models.

The study included 184 children (68 with ZZ-homozygosity, 116 with heterozygosity). The median follow-up time was 7 years [IQR 3.75-9.00] for children with ZZ-homozygosity and 0.5 years [IQR 0.0-2.0] for children with heterozygosity. Both groups had low weight-for-height Z-scores at diagnosis but experienced catch-up growth during the first year of life. In addition, children with ZZ-homozygosity had higher serum concentrations of γ-glutamyl transferase and alanine aminotransferase throughout childhood, when compared with children with heterozygosity. Data proved insufficient to assess lung function properly.

Children with ZZ-homozygosity were more affected on serum liver parameters throughout childhood when compared with children with heterozygosity. Both groups experienced catch-up growth during the first year of life.

Inborn errors of metabolism (IEMs) are a vast array of inherited/congenital disorders, affecting a wide variety of metabolic pathways and/or biochemical processes inside the cells. Although IEMs are usually rare, they can be represented as serious health problems. During the neonatal period, these inherited defects can give rise to almost all key signs of liver malfunction, including jaundice, coagulopathy, hepato- and splenomegaly, ascites, etc. Since the liver is a vital organ with multiple synthetic, metabolic, and excretory functions, IEM-related hepatic dysfunction could seriously be considered life-threatening. In this context, the identification of those hepatic manifestations and their associated characteristics may promote the differential diagnosis of IEMs immediately after birth, making therapeutic strategies more successful in preventing the occurrence of subsequent events. Among all possible liver defects caused by IEMs, cholestatic jaundice, hepatosplenomegaly, and liver failure have been shown to be manifested more frequently. Therefore, the current study aims to review substantial IEMs that mostly result in the aforementioned hepatic disorders, relying on clinical principles, especially through the first years of life. In this article, a group of uncommon hepatic manifestations linked to IEMs is also discussed in brief.

Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and can be indicative of an underlying hepatobiliary, genetic, or metabolic disorder, several of which require timely diagnosis to ensure proper management and optimal outcomes. This review provides an overview of the evaluation of cholestasis with a focus on current and emerging treatment strategies.

Increased accessibility of next generation sequencing (NGS) allows for utilization of genetic testing early in the diagnostic process. This may alter the clinical algorithm for diagnosis of cholestatic disorders. An enhanced understanding of the underlying pathophysiology may help guide future development of targeted therapies, such as ileal bile acid transporter (IBAT) inhibitors. These were recently approved for treatment of cholestatic pruritus in patients with Alagille syndrome and Progressive Familial Intrahepatic Cholestasis. Current management of cholestasis is aimed at the biochemical consequences of impaired bile flow, including malnutrition, pruritus, and progressive fibrosis. NGS has led to an enhanced understanding of biliary pathology and may guide development of future treatment modalities based on specific gene mutations. Rapid discernment of the underlying etiology is essential as new treatment modalities emerge.

Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in SERPINA1, which encodes alpha-1 antitrypsin, a protease inhibitor (Pi). Individuals with AATD and the homozygous Pi*ZZ genotype have variable risk of progressive liver disease but the influence of comorbid lung disease is poorly understood.

To characterise patients with AATD Pi*ZZ and liver disease (AATD-LD-Pi*ZZ) with or without lung disease and describe liver disease-related clinical events longitudinally.

This was an observational cohort study of patients in the Mayo Clinic Healthcare System (January 2000-September 2021). Patients were identified using diagnosis codes and natural language processing. Fibrosis stage (F0-F4) was assessed using a hierarchical approach at baseline (90 days before or after the index date) and follow-up. Clinical events associated with liver disease progression were assessed.

AATD-LD-Pi*ZZ patients with lung disease had a longer median time from AATD diagnosis to liver disease diagnosis versus those without lung disease (2.2 vs. 0.2 years, respectively). Compared to those without lung disease, patients with lung disease had a longer time to liver disease-related clinical events (8.5 years and not reached, respectively). AATD-LD-Pi*ZZ patients without lung disease were more likely to undergo liver transplantation compared with those with lung disease.

In patients with AATD and lung disease, there is a delay in the diagnosis of comorbid liver disease. Our findings suggest that liver disease may progress more rapidly in patients without comorbid lung disease.

Alpha-1 antitrypsin deficiency is a rare genetic disease and a leading cause of inherited alterations in plasma protein metabolism (APPM).

To understand the prevalence, burden and progression of liver disease in patients with APPM including alpha-1 antitrypsin deficiency.

We conducted a retrospective analysis of anonymized patient-level claims data from a German health insurance provider (AOK PLUS). The APPM cohort comprised patients with APPM (identified using the German Modification of the International Classification of Diseases-10th Revision [ICD-10-GM] code E88.0 between 01/01/2010-30/09/2020) and incident liver disease (ICD-10-GM codes K74, K70.2-3 and K71.7 between 01/01/2012-30/09/2020). The control cohort comprised patients without APPM but with incident liver disease. Outcomes were incidence/prevalence of liver disease in patients with APPM, demographics/baseline characteristics, diagnostic procedures, progression-free survival (PFS), disease progression and mortality.

Overall, 2680 and 26299 patients were included in the APPM (fibrosis, 96; cirrhosis, 2584) and control (fibrosis, 1444; cirrhosis, 24855) cohorts, respectively. Per 100000 individuals, annual incidence and prevalence of APPM and liver disease was 10-15 and 36-51, respectively. In the APPM cohort, median survival was 4.7 years [95% confidence interval (CI): 3.5-7.0] and 2.5 years (95%CI: 2.3-2.8) in patients with fibrosis and cirrhosis, respectively. A higher proportion of patients in the APPM cohort experienced disease progression (92.0%) compared with the control cohort (67.2%). Median PFS was shorter in the APPM cohort (0.9 years, 95%CI: 0.7-1.1) compared with the control cohort (3.7 years, 95%CI: 3.6-3.8; P < 0.001). Patients with cirrhosis in the control cohort had longer event-free survival for ascites, hepatic encephalopathy, hepatic failure and esophageal/gastric varices than patients with cirrhosis in the APPM cohort (P < 0.001). Patients with fibrosis in the control cohort had longer event-free survival for ascites, cirrhosis, hepatic failure and esophageal/gastric varices than patients with fibrosis in the APPM cohort (P < 0.001). In the APPM cohort, the most common diagnostic procedures within 12 mo after the first diagnosis of liver disease were imaging procedures (66.3%) and laboratory tests (51.0%).

Among patients with liver disease, those with APPM experience substantial burden and earlier liver disease progression than patients without APPM.

Alpha-1 antitrypsin deficiency (AATD) is one of the most common genetic diseases and is caused by mutations in the SERPINA1 gene. The homozygous Pi*Z variant is responsible for the majority of the classic severe form of alpha-1 antitrypsin deficiency, which is characterized by markedly decreased levels of serum alpha-1 antitrypsin (AAT) with a strong predisposition to lung and liver disease. The diagnosis and early treatment of AATD-associated liver disease are challenges in clinical practice. In this review, the authors aim to summarize the current evidence of the non-invasive methods in the assessment of liver fibrosis, as well as to elucidate the main therapeutic strategies under investigation that may emerge in the near future.

Alpha-1 antitrypsin deficiency (AATD) arises due to inherited variants in SERPINA1, the AAT gene that impairs the production or secretion of this hepatocellular protein and leads 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 to 10% of carriers as neonatal cholestasis and 20 to 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.

The prevalence of liver fibrosis detected by non-invasive imaging in alpha-1-antitrypsin (AAT) deficiency has not been systematically assessed.

We conducted a systematic review and meta-analysis to determine the prevalence of significant fibrosis and advanced fibrosis in AAT deficiency based on non-invasive imaging.

Medline and Embase electronic databases were searched for studies from inception to 13 November 2022 that provided data for the prevalence of fibrosis in adults with AAT deficiency. A generalised linear mixed model with Clopper-Pearson intervals was used to pool single-arm outcomes.

Of the 214 records identified, 8 studies were included. Five studies assessed fibrosis using vibration-controlled transient elastography. The prevalence of significant fibrosis (defined as ≥7.1 kPA) in Z homozygosity, Z heterozygosity and non-carrier status was 22.10% (five studies, 95% CI: 17.07-28.12), 9.24% (three studies, 95% CI: 4.68-17.45) and 5.38% (one study, 95% CI: 3.27-8.73), respectively, p < 0.0001, and the prevalence of advanced fibrosis (defined as ≥9.5 kPa) was 8.13% (five studies, 95% CI: 4.60-13.96), 2.96% (three studies, 95% CI: 1.49-5.81) and 1.08% (one study, 95% CI: 0.35-3.28), respectively, p = 0.003. There were limited data regarding the use of magnetic resonance elastography or acoustic radiation force impulse to assess for fibrosis.

More than one in five adult individuals with AAT deficiency and Z homozygosity harbour significant fibrosis, and nearly 1 in 10 harbours advanced fibrosis. The risk of fibrosis increases incrementally with the frequency of Pi*Z mutations.

Therapeutic agents that prevent protein misfolding or promote protein clearance are being studied to treat proteotoxic diseases. Among them, alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the alpha-1 antitrypsin (SERPINA1) gene. Fazirsiran is a small interfering RNA (siRNA) that is intended to address the underlying cause of liver disease associated with AATD through the RNA interference (RNAi) mechanism.

This article describes the role of misfolded proteins and protein aggregates in disease and options for therapeutic approaches. The RNAi mechanism is discussed, along with how the siRNA therapeutic fazirsiran for the treatment of AATD was developed. We also describe the implications of siRNA therapeutics in extrahepatic diseases.

Using RNAi as a therapeutic approach is well suited to treat disease in conditions where an excess of a protein or the effect of an abnormal mutated protein causes disease. The results observed for the first few siRNA therapeutics that were approved or are in development provide an important promise for the development of future drugs that can address such conditions in a specific and targeted way. Current developments should enable the use of RNAi therapeutics outside the liver, where there are many more possible diseases to address.

Alpha1 antitrypsin deficiency (AATD), a common hereditary disorder affecting mainly lungs, liver and skin has been the focus of some of the most exciting therapeutic approaches in medicine in the past 5 years. In this review, we discuss the therapies presently available for the different manifestations of AATD and new therapies in the pipeline.

We review therapeutic options for the individual lung, liver and skin manifestations of AATD along with approaches which aim to treat all three. Along with this renewed interest in treating AATD come challenges. How is AAT best delivered to the lung? What is the desired level of AAT in the circulation and lungs which therapeutics should aim to provide? Will treating the liver disease increase the potential for lung disease? Are there treatments to target the underlying genetic defect with the potential to prevent all aspects of AATDrelated disease?

With a relatively small population able to participate in clinical studies, increased awareness and diagnosis of AATD is urgently needed. Better, more sensitive clinical parameters will assist in the generation of acceptable and robust evidence of therapeutic effect for current and emerging treatments.

Altering the human genetic code has been explored since the early 1990s as a definitive answer for the treatment of monogenic and acquired diseases which do not respond to conventional therapies. In Alpha-1 antitrypsin deficiency (AATD) the proper synthesis and secretion of alpha-1 antitrypsin (AAT) protein is impaired, leading to its toxic hepatic accumulation along with its pulmonary insufficiency, which is associated with parenchymal proteolytic destruction. Because AATD is caused by mutations in a single gene whose correction alone would normalize the mutant phenotype, it has become a popular target for both augmentation gene therapy and gene editing. Although gene therapy products are already a reality for the treatment of some pathologies, such as inherited retinal dystrophy and spinal muscular atrophy, AATD-related pulmonary and, especially, liver diseases still lack effective therapeutic options.

Here, we review the course, challenges, and achievements of AATD gene therapy as well as update on new strategies being developed.

Reaching safe and clinically effective expression of the AAT is currently the greatest challenge for AATD gene therapy. The improvement and emergence of technologies that use gene introduction, silencing and correction hold promise for the treatment of AATD.

PiZZ (Glu342Lys) α1-antitrypsin deficiency (AATD) is characterized by intrahepatic AAT polymerization and is a risk factor for liver disease development in children. The majority of PiZZ children are disease free, hence this mutation alone is not sufficient to cause the disease. We investigated Z-AAT polymers and the expression of fibrosis-related genes in liver tissues of PiZZ children with different clinical courses. Liver biopsies obtained during 1979-2010 at the Department of Paediatrics, Karolinska University Hospital, Sweden, were subjected to histological re-evaluation, immunohistochemistry and NanoString-based transcriptome profiling using a panel of 760 fibrosis plus 8 bile acid-related genes. Subjects were divided into three groups based on clinical outcomes: NCH (neonatal cholestasis, favourable outcome, n = 5), NCC (neonatal cholestasis, early cirrhosis and liver transplantation, n = 4), and NNCH (no neonatal cholestasis, favourable outcome, n = 5, six biopsies). Hepatocytes containing Z-AAT polymers were abundant in all groups whereas NCC showed higher expression of genes related to liver fibrosis/cirrhosis and lower expression of genes related to lipid, aldehyde/ketone, and bile acid metabolism. Z-AAT accumulation per se cannot explain the clinical outcomes of PiZZ children; however, changes in the expression of specific genes and pathways involved in lipid, fatty acid, and steroid metabolism appear to reflect the degree of liver injury.

Genetic variation in alpha-1 antitrypsin (AAT) causes AAT deficiency (AATD) through liver aggregation-associated gain-of-toxic pathology and/or insufficient AAT activity in the lung manifesting as chronic obstructive pulmonary disease (COPD). Here, we utilize 71 AATD-associated variants as input through Gaussian process (GP)-based machine learning to study the correction of AAT folding and function at a residue-by-residue level by pharmacological activation of the ATF6 arm of the unfolded protein response (UPR). We show that ATF6 activators increase AAT neutrophil elastase (NE) inhibitory activity, while reducing polymer accumulation for the majority of AATD variants, including the prominent Z variant. GP-based profiling of the residue-by-residue response to ATF6 activators captures an unexpected role of the "gate" area in managing AAT-specific activity. Our work establishes a new spatial covariant (SCV) understanding of the convertible state of the protein fold in response to genetic perturbation and active environmental management by proteostasis enhancement for precision medicine.

The aim of this cross-sectional study was to assess the state of disease at the time of diagnosis in Danish children with α 1 -antitrypsin deficiency as Denmark has a high prevalence of ZZ-homozygosity.

Children either heterozygous, compound heterozygous, or homozygous for Z- and S-variants in the SERPINA1 -gene were included. Clinical characteristics, SERPINA1 -genotype, and blood serum (S) concentrations were recorded concurrently with genetic testing. Serum liver marker concentrations were compared using T tests and Wilcoxon-Mann-Whitney tests. Generalized estimating equation (GEE) linear regression models, both univariable and multivariable adjusted for age and sex, were applied to identify correlations with serum α 1 -antitrypsin (S-AAT). The relationship between S-AAT concentration and genotype was assessed using logistic regression with GEE.

The study included 183 of 225 children genetically tested for alpha-1-antitrypsin deficiency (AATD). Of these, 36.6% were homozygous for the Z-variant. Of the heterozygotes, 89.7% had a ZM genotype and the remaining had either an MS genotype or were compound heterozygous. At diagnosis, ZZ-homozygous children had higher serum concentrations of liver enzymes and conjugated bilirubin, but lower concentrations of S-AAT compared with heterozygotes. Serum concentrations of conjugated bilirubin and liver enzymes were negatively associated with S-AAT. Children under 6 months of age had higher total S-bilirubin concentrations than children over 6 months of age.

A low S-AAT concentration is a strong indicator of homozygosity, and homozygous children have higher enzymatic and cholestatic parameters compared with heterozygous children at diagnosis. This underlines the importance of measuring the S-AAT concentration in children with prolonged neonatal jaundice.

Alpha-1 antitrypsin deficiency associated liver disease (AATD-LD) is a rare genetic disorder and not well-recognized. Predicting the clinical outcomes of AATD-LD and defining patients more likely to progress to advanced liver disease are crucial for better understanding AATD-LD progression and promoting timely medical intervention. We aimed to develop a tailored machine learning (ML) model to predict the disease progression of AATD-LD. This analysis was conducted through a stacking ensemble learning model by combining five different ML algorithms with 58 predictor variables using nested five-fold cross-validation with repetitions based on the UK Biobank data. Performance of the model was assessed through prediction accuracy, area under the receiver operating characteristic (AUROC), and area under the precision-recall curve (AUPRC). The importance of predictor contributions was evaluated through a feature importance permutation method. The proposed stacking ensemble ML model showed clinically meaningful accuracy and appeared superior to any single ML algorithms in the ensemble, e.g., the AUROC for AATD-LD was 68.1%, 75.9%, 91.2%, and 67.7% for all-cause mortality, liver-related death, liver transplant, and all-cause mortality or liver transplant, respectively. This work supports the use of ML to address the unanswered clinical questions with clinically meaningful accuracy using real-world data.

Alpha₁-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency.

We assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography-mass spectrometry.

All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved.

In this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations. (Funded by Arrowhead Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.).

Alpha-1 antitrypsin deficiency (AATD) is an uncommon but underdiagnosed cause of cirrhosis and lacks medical treatment options. It is important to recognize risk factors that contribute to disease progression and liver transplantation. We aimed to assess if age, sex, or smoking status was associated with liver or lung disease progression.

Forty-three patients with ZZ-AATD cirrhosis were consecutively sampled from an Institutional Review Board-approved registry of 240 patients with AATD of any genotype seen as outpatients in the Cleveland Clinic between 1999 and 2019. To determine the association between risk factors and lung or liver disease progression, linear mixed-effects models with fixed effects for linear time, risk factor, and time-by-risk factor interaction, and the random intercepts for intra-patient correlation were used.

Based on the mixed-effects model analysis, there was a significant association between liver disease progression and smoking history, and no association with age or sex. There was no association between lung disease progression and age, sex, or smoking history. However, smoking history was significantly associated with lower forced expiratory volume values.

This study found that in a cohort of patients with PI*ZZ genotype AATD (ZZ-AATD) and cirrhosis, smoking history was associated with liver disease progression, whereas age and sex were not.

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. We also describe the mechanisms and factors promoting the development of liver disease, as well as approaches to evaluate the extent of liver fibrosis. Finally, we discuss emerging diagnostic and therapeutic approaches for the clinical management of this often neglected disorder.

Content available: Author Audio Recording.

Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.

Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.

Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.

Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.