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Objectives: It is unclear whether a distinct activity of pathways removing the antitrypsin (AT) protein in Alpha-1-Antitrypsin Deficiency (α1ATD) are associated with an unfavorable predisposition to liver disease in the future. The aim of this study was to determine whether liverspecific activity of AT protein disposal occurs at infancy in α1ATD with PiZZ phenotype (ATZ)., Methods: Liver samples of 17 infants with unfavorable ATZ outcome (Group I, n = 8, median age  = 0.35 year) and good outcome (Group II, n = 9, 0.17 year), and 9 with biliary atresia (BA, median age = 0.17 year) as control, were enrolled. For each subject were investigated autophagy activity by mRNA, protein expression (Calnexin, Beclin-1, p62, and Parkin), and hepatocyte ultrastructure with morphometric analyses., Results: No significant differences in gene expression in the liver of infants were found between the 2 ATZ groups. Although a correlation between patients' age and protein expression was observed, the ATZ groups differed Parkin immunohistochemical expression. Moreover, the hepatocytes in ATZ infants with unfavorable outcome were characterized by low Parkin expression and the presence of isolated mitophagosoms and numerous enlarged mitochondria. The mentioned findings differed in patients with BA., Conclusions: Thus, mentioned specific features occurring at infancy may suggest association with poor liver outcome. Parkin low expression could have a potential for disease prognosis and treatment; however, further studies in a greater number of patients are needed.

Severe alpha-1-antitrypsin (AAT) deficiency (PiZZ) is a risk factor for liver disease, but the prevalence of liver cirrhosis and hepatocellular cancer in PiZZ adults is unknown. The risk of liver disease in adults with moderate AAT deficiency (PiSZ) is also unknown. A cohort of 127 PiZZ, 2 PiZnull, 54 PiSZ, and 1 PiSnull individuals were identified by the Swedish national neonatal AAT screening program between 1972 and 1974, when all 200,000 newborn infants in Sweden were screened for AAT deficiency. The cohort has been followed up since birth. Our aim was to study liver function and signs of liver disease in this cohort at 37 to 40 years of age in comparison with a matched, random sample of control subjects identified from the population registry.Eighty seven PiZZ, 32 PiSZ, and 92 control subjects (PiMM) answered a questionnaire on medication and alcohol consumption and provided blood samples. Liver stiffness was assessed by Acoustic Radiation Force Impulse (ARFI) elastography in 32 PiZZ, 15 PiSZ, and 51 PiMM subjects.The median of liver function tests and procollagen-III-peptide were within the normal range in all Pi subgroups. However, the PiZZ men had significantly higher plasma bilirubin than the PiMM men (P = 0.018). Plasma [Latin Small Letter Gamma]-glutamyl transferase (GGT) was significantly higher in the PiZZ men (P = 0.009) and the PiSZ men (P = 0.021) compared with the PiMM men. The median of liver stiffness was significantly higher in the PiZZ men (P = 0.037) and the PiSZ men (P = 0.032) compared with the PiMM men. The PiZZ women taking medication influencing liver enzymes had significantly higher GGT than the PiMM women on the corresponding treatment (P = 0.023).These AAT-deficient individuals identified by neonatal screening have normal plasma levels of liver function tests, and no clinical signs indicating liver disease at the age of 37 to 40 years. However, bilirubin, GGT, and liver stiffness are significantly higher in PiZZ men than PiMM men.

Purpose of Review: The past decade has seen understanding of the molecular machinery involved in the pathogenesis of genetic hemochromatosis, Wilson's disease, and alpha1-antitrypsin deficiency grow significantly. This year has seen further progress in elaborating the molecular biology, genetics, epidemiology, and management of these inherited metabolic diseases., Recent Findings: Both Wilson's disease and genetic hemochromatosis involve defects in the transport of heavy metals and their accumulation in hepatocytes. In alpha1-antitrypsin deficiency, intrahepatocyte accumulation of defective alpha(1)-antitrypsin occurs. As a more complete picture of the molecular biology of proteins and genes involved in transport has evolved, so has our understanding of their interactions. The molecular genetics of these diseases explains the different phenotypes seen. Finally, the elucidation of the molecular pathophysiology of these diseases has led to new ideas in their clinical management., Summary: The recent developments detailed in this article have important implications for the future. Recent research has elegantly shifted the paradigm in our understanding to one focused on defects in the genetic machinery of the cell and on how better comprehension of these defects can lead to potential new therapies.

Purpose of Review: Alpha-1-antitrypsin deficiency is a relatively common genetic disease that predisposes to the development of early-onset emphysema and, in some instances, liver disease. The use of alpha-1-antitrypsin replacement therapy in the treatment of alpha-1-antitrypsin deficiency related emphysema is much debated and the purpose of this review is to examine the results of recent studies. We will comment briefly on the pathogenesis and epidemiology of the disease together with new therapeutic approaches currently under intense research., Recent Findings: Several nonrandomized observational studies and one meta-analysis on the clinical effectiveness of alpha-1-antitrypsin replacement treatment showed a favourable result towards reducing forced expiratory volume in 1 s (FEV1) deterioration in alpha-1-antitrypsin-deficient individuals with moderate lung disease or accelerated FEV1 decline. Improved ways of monitoring disease progression, including computed tomography scanning and exacerbations, are being proposed as primary endpoints. Apart from one small randomized, placebo-controlled trial using computed tomography scanning, which showed a trend toward preservation of lung density on scanning with treatment, the literature lacks proof of effectiveness from large randomized trials., Summary: There might be a possible, but so far unproven, role of alpha-1-antitrypsin augmentation therapy in reducing the progression of emphysema in subsets of patients with alpha-1-antitrypsin deficiency. Placebo-controlled, randomized clinical trials are required to draw firm conclusions. Recent advances in the understanding of the molecular pathology provide opportunities for development of new therapeutic targets for this genetic disorder.

Purpose of Review: The purpose of this review is to identify and discuss recent findings related to inherited metabolic disorders of the liver that increase our understanding of the pathophysiology and treatment for hemochromatosis and other iron overload disorders, Wilson disease and alpha one antitrypsin deficiency., Recent Findings: The main theme in the recent discoveries for both iron overload disorders and Wilson disease is our increasing understanding that the phenotypic expression of these disorders are greatly influenced by genes involved in the metabolic pathways for these metals, or influence the progression of liver disease independent of metal metabolism. For example, the role of hepcidin dysregulation in hemochromatosis has been a surprising discovery that provides some mechanistic understanding for the increased iron absorption that is present in this disorder., Summary: Given the recent explosion of information on iron and copper metabolism and the cellular processing of alpha one antitrypsin, the highlights reviewed in this article will help the reader keep up to date with the current understanding of these diseases and potential future approaches to their treatment.

The association between alpha 1-antitrypsin deficiency and heritable emphysema was discovered in 1963. Subsequent epidemiologic evidence suggested that a serum alpha 1-antitrypsin level of 11 mumol/L (about 80 mg/dL by the still-used "commercial standard"), which is about 35% of the normal level, represents a "threshold" value, below which the risk of developing emphysema is increased and above which the emphysema risk is not increased. Recently, the ability to isolate and purify the alpha 1-antitrypsin protein from human blood has made "specific" augmentation therapy possible. Intravenous infusion of alpha 1-antitrypsin raises serum and alveolar levels above the putative thresholds, but clinical efficacy (i.e., decreased rate of decline in lung function and/or improved survival) remains presumptive. Based on available evidence, the American Thoracic Society recommends augmentation therapy for individuals with both a documented severe deficiency of alpha 1-antitrypsin and fixed airflow obstruction.