Autophagy in liver diseases: Time for translation?

Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role in energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy. Indeed, enhancing autophagy may prevent the progression of a number of liver diseases, including storage disorders (alpha-1 antitrypsin deficiency, Wilson's disease), acute liver injury, non-alcoholic steatohepatitis and chronic alcohol-related liver disease. Nevertheless, in some situations such as fibrosis, targeting specific liver cells must be considered, as autophagy displays opposing functions depending on the cell type. In addition, an optimal therapeutic time-window should be identified, since autophagy might be beneficial in the initial stages of disease, but detrimental at more advanced stages, as in the case of hepatocellular carcinoma. Finally, identifying biomarkers of autophagy and methods to monitor autophagic flux in vivo are important steps for the future development of personalized autophagy-targeting strategies. In this review, we provide an update on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagy and discussing the potential to modulate autophagy as a therapeutic strategy in the context of liver diseases.

hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency.

BACKGROUND & AIMS: α1-Antitrypsin deficiency (A1ATD) is an autosomal recessive disorder caused by mutations in the SERPINA1 gene. Individuals with the Z variant (Gly342Lys) retain polymerised protein in the endoplasmic reticulum (ER) of their hepatocytes, predisposing them to liver disease. The concomitant lack of circulating A1AT also causes lung emphysema. Greater insight into the mechanisms that link protein misfolding to liver injury will facilitate the design of novel therapies. METHODS: Human-induced pluripotent stem cell (hiPSC)-derived hepatocytes provide a novel approach to interrogate the molecular mechanisms of A1ATD because of their patient-specific genetic architecture and reflection of human physiology. To that end, we utilised patient-specific hiPSC hepatocyte-like cells (ZZ-HLCs) derived from an A1ATD (ZZ) patient, which faithfully recapitulated key aspects of the disease at the molecular and cellular level. Subsequent functional and "omics" comparisons of these cells with their genetically corrected isogenic-line (RR-HLCs) and primary hepatocytes/human tissue enabled identification of new molecular markers and disease signatures. RESULTS: Our studies showed that abnormal A1AT polymer processing (immobilised ER components, reduced luminal protein mobility and disrupted ER cisternae) occurred heterogeneously within hepatocyte populations and was associated with disrupted mitochondrial structure, presence of the oncogenic protein AKR1B10 and two upregulated molecular clusters centred on members of inflammatory (IL-18 and Caspase-4) and unfolded protein response (Calnexin and Calreticulin) pathways. These results were validated in a second patient-specific hiPSC line. CONCLUSIONS: Our data identified novel pathways that potentially link the expression of Z A1AT polymers to liver disease. These findings could help pave the way towards identification of new therapeutic targets for the treatment of A1ATD. LAY SUMMARY: This study compared the gene expression and protein profiles of healthy liver cells and those affected by the inherited disease α1-antitrypsin deficiency. This approach identified specific factors primarily present in diseased samples which could provide new targets for drug development. This study also demonstrates the interest of using hepatic cells generated from human-induced pluripotent stem cells to model liver disease in vitro for uncovering new mechanisms with clinical relevance.

The first report of two cases of fatal liver injury due to anti-tuberculosis drugs in the presence of alpha-1 antitrypsin deficiency.

Tuberculosis (TB) is a major global health problem. Awareness of liver injury due to anti-TB therapy is vital because fulminant hepatic failure is a devastating and often fatal condition without liver transplantation. Here, we report for the first time, two patients of fatal liver injury due to anti-TB drugs in the presence of alpha-1 antitrypsin deficiency. Based on the triad of rapid loss in hepatocyte function, the onset of hepatic encephalopathy, and absence of a prior history of liver disease, the diagnosis of acute liver failure was established. Both patients had low levels of serum alpha-1 antitrypsin, consistent with alpha-1 antitrypsin deficiency. Despite aggressive medical therapy and supportive care, patients developed multi-organ failure and died. It seems measuring the serum levels of alpha 1-antitrypsin before beginning anti-TB therapies is necessary, especially when there is emphysema or bronchiectasis.

Vasculitis con Anticuerpos anticitoplasma de neutrófilos (ANCA) negativos en paciente con déficit de alfa-1 antitripsina / Antineutrophil cytoplasmic antibodies (ANCA)-negative vasculitis in a patient with alpha-1-antitrypsin deficiency

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Déficit combinado de alfa-1-antitripsina y déficit de lectina fijadora de manosa / Combined alpha-1-antitrypsin deficiency and mannose-binding lectin deficiency

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Suspecting and Testing for Alpha-1 Antitrypsin Deficiency-An Allergist's and/or Immunologist's Perspective.

Alpha-1 antitrypsin deficiency (AATD) is a hereditary, monogenic disorder with no unique clinical features. AATD can be difficult to diagnose as patients commonly present with respiratory symptoms often mistaken for other respiratory syndromes such as asthma or smoking-related chronic obstructive pulmonary disease. In addition, symptoms related to AATD may also affect other organs, including the liver, vasculature, and skin. The severity of AATD varies between individuals, and in severe cases, the irreversible lung damage can develop into emphysema. Early diagnosis is critical to enable the implementation of lifestyle changes and therapeutic options that can slow further deterioration of pulmonary tissue. Once AATD is suspected, a range of tests are available (serum alpha-1 proteinase inhibitor [A1-PI] level measurement, phenotyping, genotyping, gene sequencing) for confirming AATD. Currently, intravenous infusion of A1-PI is the only therapy that directly addresses the underlying cause of AATD, and has demonstrated efficacy in a recent randomized, placebo-controlled trial. This review discusses the etiology, testing, and management of AATD from the allergist's and/or immunologist's perspective. It aims to raise awareness of the condition among physicians who care for people with obstructive lung disorders and are therefore likely to see patients with obstructive lung disease that may, in fact, prove to be AATD.

Maternal uniparental disomy 14 revealed by alpha 1 antitrypsin deficiency.

UNLABELLED: Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disease linked to a mutation of the SERPINA1 gene localized to chromosome 14q32. Uniparental disomy (UPD) is known to be a genetic mechanism that causes various syndromes. Maternal UPD14 presents with a Prader-Willi syndrome-like phenotype. No publications to date have dealt with the association of these two syndromes. In this article, we report on two cases of AATD (from different families), which lead to the diagnosis of maternal UPD14. AATD was diagnosed early in both children. Their clinical presentations were typical (chronic cytolysis in patient 1 and neonatal cholestasis in patient 2); serum alpha 1 antitrypsin levels were low (P1 0.33g/L and P2 0.35g/L), and both patients had a Z phenotype. A pedigree study of both families showed that the father had an M phenotype and the mother an MZ phenotype, which was unexpected. On the other hand, both children were born before term and presented with symmetrical growth retardation, early eating difficulties, moderate hypotonia, understated dysmorphic features and moderate psychomotor retardation, suggestive of a Prader-Willi syndrome-like phenotype. Genotyping was performed to explain gene transmission inconsistencies, and highlighted maternal UPD 14 in both families. CONCLUSION: Logically, maternal UPD 14 can induce AATD. In light of these observations, it seems appropriate to search for AATD in patients with maternal UPD 14 in order to prevent a progression of the disease. These cases also underline the significance of maternal UPD 14, which should be suspected in AATD in view of the discordance with Mendel's allelic transmission law.

The molecular and cellular pathology of α1-antitrypsin deficiency.

Since its discovery 50 years ago, α1-antitrypsin deficiency has represented a case study in molecular medicine, with careful clinical characterisation guiding genetic, biochemical, biophysical, structural, cellular, and in vivo studies. Here we highlight the milestones in understanding the disease mechanisms and show how they have spurred the development of novel therapeutic strategies. α1-Antitrypsin deficiency is an archetypal conformational disease. Its pathogenesis demonstrates the interplay between protein folding and quality control mechanisms, with aberrant conformational changes causing liver and lung disease through combined loss- and toxic gain-of-function effects. Moreover, α1-antitrypsin exemplifies the ability of diverse proteins to self-associate into a range of morphologically distinct polymers, suggesting a mechanism for protein and cell evolution.

Alpha-1 antitrypsin deficiency in patients with chronic hepatitis.

BACKGROUND/AIMS: Alpha-1 antitrypsin deficiency causes accumulation of mutant alpha-1 antitrypsin molecules in hepatocytes, and is attributed to severe liver injury even in heterozygous state. However, there is a question as to whether alpha-1 antitrypsin deficiency is only a cause of liver injury or has a worsening effect on the underlying liver disease. We aimed to determine the role of alpha-1 antitrypsin deficiency in the ongoing chronic hepatitic process. MATERIALS AND METHODS: Fifty-four patients with the diagnosis of chronic hepatitis by liver biopsy (36 chronic hepatitis B virus, 8 chronic hepatitis C virus, 7 non-alcoholic steatohepatitis, 2 primary biliary cirrhosis, and 1 autoimmune hepatitis) and 51 age- and sex-matched control subjects chosen from among healthy blood donors were included in the study. Isoelectric focusing for identifying alpha-1 antitrypsin phenotypes was performed in all patients and control subjects, whereas the histopathological examination was done only in patients. RESULTS: Alpha-1 antitrypsin-deficient variant was absent in patients and controls. The mean serum alpha-1 antitrypsin level was significantly lower in patients (157.4 ± 33 mg/dl) than controls (134.8 ± 30 mg/dl) (p<0.00). Histological activity index and fibrosis grade in the liver were not related to the serum alpha-1 antitrypsin level (p: 0.276 and 0.902, respectively). Additionally, the serum alpha-1 antitrypsin levels among normal variants of alpha-1 antitrypsin did not differ according to the underlying liver diseases (p: 0.928). CONCLUSIONS: This prospective case-control study could not define any additional effect of alpha-1 antitrypsin deficiency on liver histopathology in chronic hepatitis patients.

SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort.

BACKGROUND: Severe alpha1-antitrypsin (AAT) deficiency is a strong risk factor for COPD. But the impact of gene variants resulting in mild or intermediate AAT deficiency on the longitudinal course of respiratory health remains controversial. There is indication from experimental studies that pro-inflammatory agents like cigarette smoke can interact with these variants and thus increase the risk of adverse respiratory health effects. Therefore, we tested the effect of the presence of a protease inhibitor (Pi) S or Z allele (PiMS and PiMZ) on the change in lung function in different inflammation-exposed subgroups of a large, population-based cohort study. METHODOLOGY AND PRINCIPAL FINDINGS: The SAPALDIA population includes over 4600 subjects from whom SERPINA1 genotypes for S and Z alleles, spirometry and respiratory symptoms at baseline and after 11 years follow-up, as well as proxies for inflammatory conditions, such as detailed smoking history, obesity and high sensitivity C-reactive protein (hs-CRP), were available. All analyses were performed by applying multivariate regression models. There was no overall unfavourable effect of PiMS or PiMZ genotype on lung function change. We found indication that PiZ heterozygosity interacted with inflammatory stimuli leading to an accelerated decline in measures in use as indices for assessing mild airway obstruction. Obese individuals with genotype PiMM had an average annual decline in the forced mid expiratory flow (ΔFEF25-75%) of 58.4 ml whereas in obese individuals with PiMZ it amounted to 92.2 ml (p = 0.03). Corresponding numbers for persistent smokers differed even more strongly (66.8 ml (PiMM) vs. 108.2 ml (PiMZ), p = 0.005). Equivalent, but less strong associations were observed for the change in the FEV1/FVC ratio. CONCLUSIONS: We suggest that, in addition to the well established impact of the rare PiZZ genotype, one Z allele may be sufficient to accelerate lung function decline in population subgroups characterized by elevated levels of low grade inflammation.

Acquired alpha 1-antitrypsin deficiency in tropical pulmonary eosinophilia.

BACKGROUND & OBJECTIVES: Observation of an increased frequency of an intermediate deficiency of serum alpha1-antitrypsin (α1-AT) in patients with Tropical Pulmonary Eosinophilia (TPE) was earlier reported. Though the possibility of existence of an acquired deficiency was suggested, without phenotyping a hereditary α1-AT deficiency in TPE could not totally be ruled out. In this study, we have done Pi (Protease inhibitor) phenotyping to investigate the possibility of association of any heterozygous (or homozygous) α1-AT deficiency in patients with TPE. METHODS: Serum a1antitrypsin (α1-AT) was measured in 103 patients (Group A) with TPE, 99 patients with pulmonary eosinophilia who had associated intestinal worm infestation (Group B) and 43 healthy volunteers who served as controls. In 19 α1-AT deficient patients (9 of Group A and 10 of Group B), α1-AT level was measured before and after treatment. In 58 patients with TPE and in 5 controls, phenotyping was done. RESULTS: Fifteen patients of Group A and 16 from Group B showed intermediate α1-AT deficiency (150 mg % or less. None of the control subjects had α1-AT deficiency (<200 mg%). After treatment with DEC and/or deworming, in 19 patients there was a significant (P < 0.001) rise in α1-AT levels. Results of phenotyping showed that all had M1 or M 2 allele and none had S or Z variant (either homozygous or heterozygous) thus ruling out any underlying genetic cause for the observed α1-AT deficiency. INTERPRETATION & CONCLUSIONS: The observed α1-AT deficiency may be due to the chronic inflammation in TPE and associated oxidative stress. However, in such α1-AT deficient patients with TPE and those with worm infested pulmonary eosinophilia, faecal α1-AT concentration and faecal α1-AT clearance should be routinely estimated to rule out the possibility of any intestinal protein loss.

Accelerated spirometric decline in New York City firefighters with α1-antitrypsin deficiency.

BACKGROUND: On September 11, 2001, the World Trade Center (WTC) collapse caused massive air pollution, producing variable amounts of lung function reduction in the New York City Fire Department (FDNY) rescue workforce. α1-Antitrypsin (AAT) deficiency is a risk factor for obstructive airway disease. METHODS: This prospective, longitudinal cohort study of the first 4 years post-September 11, 2001, investigated the influence of AAT deficiency on adjusted longitudinal spirometric change (FEV1) in 90 FDNY rescue workers with WTC exposure. Workers with protease inhibitor (Pi) Z heterozygosity were considered moderately AAT deficient. PiS homozygosity or PiS heterozygosity without concomitant PiZ heterozygosity was considered mild deficiency, and PiM homozygosity was considered normal. Alternately, workers had low AAT levels if serum AAT was ≤ 20 µmol/L. RESULTS: In addition to normal aging-related decline (37 mL/y), significant FEV(1) decline accelerations developed with increasing AAT deficiency severity (110 mL/y for moderate and 32 mL/y for mild) or with low AAT serum levels (49 mL/y). Spirometric rates pre-September 11, 2001, did not show accelerations with AAT deficiency. Among workers with low AAT levels, cough persisted in a significant number of participants at 4 years post-September 11, 2001. CONCLUSIONS: FDNY rescue workers with AAT deficiency had significant spirometric decline accelerations and persistent airway symptoms during the first 4 years after WTC exposure, representing a novel gene-by-environment interaction. Clinically meaningful decline acceleration occurred even with the mild serum AAT level reductions associated with PiS heterozygosity (without concomitant PiZ heterozygosity).

Improving diagnosis and management of alpha-1 antitrypsin deficiency in primary care: translating knowledge into action.

Alpha-1 antitrypsin (AAT) deficiency is an established genetic risk factor for pulmonary disease and may lead to severe emphysema. Despite accessible, inexpensive, and straightforward testing procedures, the disorder is still widely undiagnosed due mainly to a lack of awareness among the medical community. AAT deficiency often results in the development of non-specific respiratory symptoms that can be confused with those of other non-hereditary chronic obstructive pulmonary disease or asthma. However, there are published guidelines that provide detailed recommendations on patient testing. Early diagnosis of AAT deficiency is fundamental to improve patient outcomes; it allows preventive measures to be taken, such as smoking cessation, and allows monitoring and initiation of appropriate therapy while lung function is still relatively preserved. Diagnosis should not solely be the domain of the specialist pulmonologist; testing can be easily initiated in the primary care setting. The establishment of process maps and diagnosis algorithms, as suggested in this review, should encourage appropriate suspicion, testing, and follow-up of AAT deficiency in the patient's primary care medical home setting. Primary care physicians have a key role in increasing the awareness, diagnosis, and effective management of this disorder.

Exacerbations in subjects with alpha-1 antitrypsin deficiency receiving augmentation therapy.

BACKGROUND: The frequency, characteristics and impact of acute exacerbations in patients with alpha-1 antitrypsin deficiency (AATD) and COPD who are on intravenous alpha-1 antitrypsin augmentation therapy have not been described. METHODS: 922 subjects with AATD and COPD on augmentation therapy (mean age 54.5 years) were followed with monthly telephone surveys to record exacerbation characteristics, as well as healthcare resource utilization and health-related quality of life (HRQoL). Exacerbations were defined by symptom-based and healthcare resource utilization (HRU) criteria. RESULTS: During the 1-year follow-up, 91.5% of participants experienced at least one exacerbation (mean 2.4 exacerbations per subject, median 2, and mean duration 17 days per episode, regardless of the definition used). Most exacerbations were categorized as severe by symptoms and moderate by HRU criteria. Subjects who had 3 or more exacerbations (48.6%) were younger, had higher medication use and had higher tobacco consumption compared with subjects with less exacerbations. Subjects with frequent exacerbations had the worst baseline HRQoL scores, as well as more physician visits, emergency room visits, and hospitalizations. Although most subjects received augmentation therapy on a weekly basis, other infusion schedules were more commonly observed in subjects with fewer exacerbations. CONCLUSION: COPD exacerbations occur frequently and are associated with significant disease burden in subjects with AATD receiving augmentation therapy.

Serpin polymerization and its role in disease--the molecular basis of alpha1-antitrypsin deficiency.

Protein aggregation is the cause of several human diseases. Understanding the molecular mechanisms involved in protein aggregation requires knowledge of the kinetics and structures populated during the reaction. Arguably, the best structurally characterized misfolding reaction is that of alpha(1)-antitrypsin. Alpha(1)-antitrypsin misfolding leads to both liver disease and emphysema and affect approximately 1 in 2000 of the population. This review will focus on the mechanism of alpha(1)-antitrypsin misfolding and the development of potential therapeutic strategies.

Coagulopatía como presentación inicial de un déficit de alfa 1 antitripsina / Coagulopathy as initial presentation of an alpha 1 antitryipsin deficiency

El déficit de alfa-1 antitripsina es una enfermedad genética causada por la alteración del gen de un inhibidor de la proteasa de los neutrófilos localizado en el cromosoma14. Su expresividad clínica es variable: hepatitis colestásicaneo natal, ictericia, hipertransaminasemia o incluso cirrosis juvenil. El diagnóstico de sospecha se basa en la detecciónde niveles disminuidos de alfa-1 antitripsina y se confirma mediante fenotipificación de la proteína (electroforesis)y estudio genético. Presentamos el caso de un lactante de mes y medio que presentó un gran hematoma en la zona de punción de una vacuna. La analítica demostró una alteración de la coagulación asociado a un patrón de hepatitis colestásica. Los niveles de alfa-1 antitripsina fueron de 54 mg/dl y un fenotipo Pi tipo SZ. Se trató con factor VII activado recombinante, suplementos de vitaminas liposolubles y ácido ursodesoxicólico con buena evolución .La ictericia neonatal puede ser signo de colestasis por lo que debe determinarse la bilirrubina total y conjugada en todo neonato con ictericia persistente (AU)

Alpha-1 antitrypsin is an inhibitor of the protease of the neutrophils. Alpha-1 antitrypsin deficiency is a genetic disorder caused by the alteration of the gene in chromosome14 which codifies this protein. Clinical manifestations may vary: neonatal cholestatic hepatitis, jaundice, hypertransaminasemia or even childhood cirrhosis. Diagnosis is based on alpha-1 antitrypsin levels and it is confirmed bythe phenotype of the protein (electrophoresis) and genetic study. We describe the case of a six weeks old infant seen in our emergency department due to a haematoma surrounding avaccine puncture point. Blood analysis revealed a coagulopathy associated to cholestatic hepatitis. The levels ofalpha-1 antitrypsin were 54 mg/dl and the phenotype was Pi SZ. He was treated with recombinant factor VIIa, fat soluble vitamins and ursodeoxicolic acid, with a good evolution. Neonatal jaundice may indicate cholestasis, so in a newborn with persistent jaundice a measurement of the serum total and conjugated bilirub in is mandatory (AU)

Results of lung transplantation in patients with cystic fibrosis.

Lung transplantation (LT) is the only available option for patients with cystic fibrosis (CF) with end-stage lung disease. We reviewed our experience with LT in patients with end-stage CF (CFLT) to identify variables associated with survival and to compare the results with other indications for LT (OILT). Between October 1993 and October 2007, we performed 259 consecutive LTs in 250 patients for treatment of various end-stage pulmonary conditions. The indications for LT were CF in 78 patients idiopathic pulmonary fibrosis in 76, COPD in 64, bronchiectasis in 11, alfa-1-antitrypsin deficit in 5, primary pulmonary hypertension in 4, bronchiolitis obliterans syndrome in 4, and other indications in 11. Our study group comprised 78 patients with CF (30.11%) (CFLT). We observed significant differences in the actuarial survival between the CFLT and OILT groups. Perioperative mortality and the incidence of bronchiolitis obliterans syndrome were comparable in both groups. We found that in patients with CF, LT performed under urgency code (mechanical ventilation) showed no significant difference from LT performed electively insofar as long-term survival, early death, or perioperative death. The functional results in the CFLT group were excellent. We observed significant improvement in PaO(2), PaCO(2), forced vital capacity, and forced expiratory volume in the first second of expiration at 6, 12, and 36 months compared with the pretransplantation baseline values.

[Exocrin pancreatic deficiency revealing an alpha-1-antitrypsin deficiency]. / Insuffisance pancréatique exocrine révélant un déficit en alpha-1-antitrypsine.

There are genetic mutations taking part in the physiopathology of pancreatitis. The role of alpha-1-antitrypsin (AAT) deficiency in this pathology is debated. We report the case of a 60-year-old man with a pancreatic exocrine insufficiency. He was diagnosed with AAT deficiency. The phenotype was Pi SZ, with genotyping confirmation. The place of AAT deficiency in the midst of pancreatic diseases should be further studied.

AANA journal course. Update for nurse anesthetists--part 4--life in the balance: the role of serpins in disease genesis and prevention.

Complex biological systems are often shaped and maintained by opposing forces. A relevant biological example is the delicate balance between proteases and their inhibitors. Serine proteases contain a serine residue in the active site of the molecule that is essential to the activity of the enzyme. Protease inhibitors limit the activity of proteases in the body. As examples, aprotinin (Trasylol), a serine protease inhibitor, and aminocaproic acid (Amicar), a lysine protease inhibitor, are used to decrease the rate of fibrinolysis and have recently been the subject of considerable controversy in the literature regarding safety and efficacy. This AANA journal course reviews 2 common examples of protease inhibitor disorders, angioedema and a form of emphysema, that are of particular anesthetic relevance.