Liver Transplantation for Advanced Liver Disease with Alpha-1antitrypsin Deficiency

ALPHA-1-antitrypsin deficiency associated with chronic obstructive airway disease was recognized in 1963 by Laurell and Ericksson.1 In 1969, Sharp2 described the first cases of alpha-1-antitrypsin-deficiency disease in children with cirrhosis. Since then, this inborn error has been recognized as one of the more common factors in cirrhosis of infancy and childhood,3 including “neonatal hepatitis.”4 Alpha-1-antitrypsin is a glycoprotein that accounts for a major portion of the alpha-1 globulin fraction of the serum.5 It is responsible for approximately 90 per cent of the antitrypsin activity6 of the serum, and it also inhibits several other plasma enzymes, including plasmin,7 elastase,8 collagenase,9 and. © 1980, Massachusetts Medical Society. All rights reserved

Elevated NET, Calprotectin, and Neopterin Levels Discriminate between Disease Activity in COVID-19, as Evidenced by Need for Hospitalization among Patients in Northern Italy

Coronavirus disease 2019 (COVID-19) displays clinical heterogeneity, but little information is available for patients with mild or very early disease. We aimed to characterize biomarkers that are useful for discriminating the hospitalization risk in a COVID-19 cohort from Northern Italy during the first pandemic wave. We enrolled and followed for four weeks 76 symptomatic SARS-CoV-2 positive patients and age/sex-matched healthy controls. Patients with mild disease were discharged (n.42), and the remaining patients were hospitalized (n.34). Blood was collected before any anti-inflammatory/immunosuppressive therapy and assessed for soluble C5b-9/C5a, H3-neutrophil extracellular traps (NETs), calprotectin, and DNase plasma levels via ELISA and a panel of proinflammatory cytokines via ELLA. Calprotectin and NET levels discriminate between hospitalized and non-hospitalized patients, while DNase negatively correlates with NET levels; there are positive correlations between calprotectin and both NET and neopterin levels. Neopterin levels increase in patients at the beginning of the disease and do so more in hospitalized than non-hospitalized patients. C5a and sC5b-9, and other acute phase proteins, correlate with neopterin, calprotectin, and DNase. Both NET and neopterin levels negatively correlate with platelet count. We show that calprotectin, NETs, and neopterin are important proinflammatory parameters potentially useful for discriminating between COVID-19 patients at risk of hospitalization

Calprotectin (S100A8/S100A9) and Myeloperoxidase: Co-Regulators of Formation of Reactive Oxygen Species

Inflammatory mediators trigger polymorphonuclear neutrophils (PMN) to produce reactive oxygen species (ROS: O2-, H2O2, ∙OH). Mediated by myeloperoxidase in PMN, HOCl is formed, detectable in a chemiluminescence (CL) assay. We have shown that the abundant cytosolic PMN protein calprotectin (S100A8/A9) similarly elicits CL in response to H2O2 in a cell-free system. Myeloperoxidase and calprotectin worked synergistically. Calprotectin-induced CL increased, whereas myeloperoxidase-triggered CL decreased with pH > 7.5. Myeloperoxidase needed NaCl for CL, calprotectin did not. 4-hydroxybenzoic acid, binding ∙OH, almost abrogated calprotectin CL, but moderately increased myeloperoxidase activity. The combination of native calprotectin, or recombinant S100A8/A9 proteins, with NaOCl markedly enhanced CL. NaOCl may be the synergistic link between myeloperoxidase and calprotectin. Surprisingly- and unexplained- at higher concentration of S100A9 the stimulation vanished, suggesting a switch from pro-oxidant to anti-oxidant function. We propose that the ∙OH is predominant in ROS production by calprotectin, a function not described before

Hereditary alpha-1-antitrypsin deficiency and its clinical consequences

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave

Faecal calprotectin concentrations in apparently healthy children aged 0-12 years in urban Kampala, Uganda: a community-based survey

<p>Abstract</p> <p>Background</p> <p>Calprotectin is a calcium and zinc binding protein, abundant in neutrophils and is extremely stable in faeces. Faecal calprotectin is used as a non-specific marker for gastrointestinal inflammation. It has a good diagnostic precision to distinguish between irritable bowel syndrome and inflammatory bowel disease. Studies have established normal concentrations in healthy children; all these studies have been performed in high-income countries. The objective of this study was to determine the concentration of faecal calprotectin in apparently healthy children aged 0-12 years in urban Kampala, Uganda.</p> <p>Method</p> <p>We tested 302 apparently healthy children aged, age 0-12 years (162 female, 140 male) in urban Kampala, Uganda. The children were recruited consecutively by door-to-door visits. Faecal calprotectin was analyzed using a quantitative enzyme-linked immunosorbent assay. Faeces were also tested for <it>Helicobacter pylori (H. pylori) </it>antigen, for growth of enteropathogens and microscopy was performed to assess protozoa and helminths. A short standardized interview with socio-demographic information and medical history was obtained to assess health status of the children.</p> <p>Results</p> <p>In the different age groups the median faecal calprotectin concentrations were 249 mg/kg in 0 < 1 year (n = 54), 75 mg/kg in 1 < 4 years (n = 89) and 28 mg/kg in 4 < 12 years (n = 159). There was no significant difference in faecal calprotectin concentrations and education of female caretaker, wealth index, gender, habits of using mosquito nets, being colonized with <it>H. pylori </it>or having other pathogens in the stool.</p> <p>Conclusion</p> <p>Concentrations of faecal calprotectin among healthy children, living in urban Ugandan, a low-income country, are comparable to those in healthy children living in high-income countries. In children older than 4 years, the faecal calprotectin concentration is low. In healthy infants faecal calprotectin is high. The suggested cut-off concentrations in the literature can be used in apparently healthy Ugandan children. This finding also shows that healthy children living under poor circumstances do not have a constant inflammation in the gut. We see an opportunity to use this relatively inexpensive test for further understanding and investigations of gut inflammation in children living in low-income countries.</p

The genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by the interaction of genetic susceptibility and environmental influences. There is increasing evidence that genes link to disease pathogenesis and heterogeneity by causing variation in protease anti-protease systems, defence against oxidative stress and inflammation. The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation

Sputum and serum calprotectin are useful biomarkers during CF exacerbation

AbstractBackgroundAdequate monitoring of cystic fibrosis lung disease is difficult. CF exacerbation offers a unique setting to test the utility of biomarkers in the assessment of changing airways inflammation. We hypothesised that levels of calprotectin in sputum (and serum) would change informatively following treatment of an exacerbation.Methods27 patients with CF were recruited at onset of pulmonary exacerbation. Sputum and serum were collected at the start and end of anti-biotic therapy. Sputum calprotectin, interleukin-8 (IL8), and myeloperoxidase (MPO) were measured, as were serum calprotectin, CRP and vascular endothelial growth factor (VEGF).ResultsSputum calprotectin decreased following treatment of an exacerbation (p<0.05), and was superior to other sputum markers. Serum calprotectin, CRP, and VEGF also decreased significantly (p=0.002, p=0.002, p=0.013 respectively). Serum calprotectin level following treatment had predictive value for time to next exacerbation (p=0.032).ConclusionsThis study demonstrates the superiority of calprotectin (in sputum and serum) as a biomarker of CF exacerbation over better-established markers

The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote

BackgroundInheritance of the F variant of alpha-1-antitrypsin is associated with normal circulating protein levels, but it is believed to be dysfunctional in its ability to inhibit neutrophil elastase and therefore has been implicated as a susceptibility factor for the development of emphysema. In this study, its functional characteristics were determined following the identification of a unique patient with the PiFF phenotype, and the implications as a susceptibility factor for emphysema are considered both in homozygotes and heterozygotes.MethodsSecond order association rate constants were measured for M, Z, S and F variants of alpha-1-antitrypsin with neutrophil elastase and proteinase 3. Clinical characteristics of the PiFF homozygote and six PiFZ heterozygote subjects were studied.ResultsThe F variant had a reduced association rate constant with neutrophil elastase (5.60???0.83 ? 106 M-1?s-1) compared to the normal M variant (1.45???0.02 ? 107 M-1?s-1), indicating an increased time to inhibition that was comparable to that of the Z variant (7.34???0.03 ? 106 M-1?s-1). The association rate constant for the F variant and proteinase 3 (1.06???0.22 ? 106 M-1?s-1) was reduced compared to that with neutrophil elastase, but was similar to that of other alpha-1-antitrypsin variants. Of the six PiFZ heterozygotes, five had airflow obstruction and radiological evidence of emphysema. The PiFF homozygote had airflow obstruction but no emphysema. None of the patients had clinical evidence of liver disease.ConclusionsThe F variant may increase susceptibility to elastase-induced lung damage but not emphysema, whereas co-inheritance with the Z deficiency allele may predispose to emphysema despite reasonable plasma concentrations of alpha-1-antitrypsin