Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321375
Author(s):  
Christoph Grander ◽  
Benedikt Schaefer ◽  
Julian Schwärzler ◽  
Felix Grabherr ◽  
Dennis M de Graaf ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Liver Injury ◽  
Serum Concentration ◽  
Neutrophil Infiltration ◽  
Serum Concentrations ◽  
Cox Regression Analysis ◽  
Alpha 1 Antitrypsin ◽  
Related Liver Disease

ObjectiveAlcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.DesignAn unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models.ResultsCirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis.ConclusionCirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.

Serum Concentration and Skin Expression of S100A7 (Psoriasin) in Patients Suffering from Hidradenitis Suppurativa

Dermatology ◽  
2020 ◽  
pp. 1-7
Author(s):  
Aleksandra Batycka-Baran ◽  
Wojciech Baran ◽  
Danuta Nowicka-Suszko ◽  
Maria Koziol-Gałczyńska ◽  
Andrzej Bieniek ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Hidradenitis Suppurativa ◽  
Protein Concentration ◽  
Normal Skin ◽  
Innate Immune ◽  
Antimicrobial Protein ◽  
Healthy Controls ◽  
Serum Concentrations ◽  
Reactive Protein

<b><i>Background:</i></b> Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. An important role of innate immune dysregulation in the pathogenesis of HS has been highlighted. S100A7 (psoriasin) is an innate, antimicrobial protein that exerts proinflammatory and chemotactic action. <b><i>Objectives:</i></b> The objective of the study was to investigate serum concentrations of S100A7 in individuals with HS as compared to healthy controls. Further, we evaluated the expression of S100A7 in lesional HS skin as compared to perilesional (clinically uninvolved) HS skin and normal skin. <b><i>Methods:</i></b> Serum concentrations of S100A7 were evaluated with a commercially available ELISA kit. The expression of S100A7 in the skin was assessed using qRT-PCR and immunofluorescence staining. <b><i>Results:</i></b> We found increased expression of S100A7 in lesional HS skin as compared to perilesional HS skin (<i>p</i> = 0.0017). The expression of S100A7 in lesional HS skin was positively associated with serum C-reactive protein concentration and the severity of disease according to Hurley staging. The serum concentration of S100A7 in individuals with HS was decreased as compared to healthy controls and patients with psoriasis. <b><i>Conclusions:</i></b> Upregulated in lesional HS skin, S100A7 may enhance the inflammatory process and contribute to the HS pathogenesis.

scholarly journals Possible unrecognised liver injury is associated with mortality in critically ill COVID-19 patients

2021 ◽  
Vol 14 ◽  
pp. 175628482110234
Author(s):  
Mario Romero-Cristóbal ◽  
Ana Clemente-Sánchez ◽  
Patricia Piñeiro ◽  
Jamil Cedeño ◽  
Laura Rayón ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Liver Injury ◽  
Chronic Liver Disease ◽  
Critically Ill ◽  
Cox Regression ◽  
Chronic Liver ◽  
Cox Regression Analysis ◽  
Risk Of Death ◽  
The Impact

Background: Coronavirus disease (COVID-19) with acute respiratory distress syndrome is a life-threatening condition. A previous diagnosis of chronic liver disease is associated with poorer outcomes. Nevertheless, the impact of silent liver injury has not been investigated. We aimed to explore the association of pre-admission liver fibrosis indices with the prognosis of critically ill COVID-19 patients. Methods: The work presented was an observational study in 214 patients with COVID-19 consecutively admitted to the intensive care unit (ICU). Pre-admission liver fibrosis indices were calculated. In-hospital mortality and predictive factors were explored with Kaplan–Meier and Cox regression analysis. Results: The mean age was 59.58 (13.79) years; 16 patients (7.48%) had previously recognised chronic liver disease. Up to 78.84% of patients according to Forns, and 45.76% according to FIB-4, had more than minimal fibrosis. Fibrosis indices were higher in non-survivors [Forns: 6.04 (1.42) versus 4.99 (1.58), p < 0.001; FIB-4: 1.77 (1.17) versus 1.41 (0.91), p = 0.020)], but no differences were found in liver biochemistry parameters. Patients with any degree of fibrosis either by Forns or FIB-4 had a higher mortality, which increased according to the severity of fibrosis ( p < 0.05 for both indexes). Both Forns [HR 1.41 (1.11–1.81); p = 0.006] and FIB-4 [HR 1.31 (0.99–1.72); p = 0.051] were independently related to survival after adjusting for the Charlson comorbidity index, APACHE II, and ferritin. Conclusion: Unrecognised liver fibrosis, assessed by serological tests prior to admission, is independently associated with a higher risk of death in patients with severe COVID-19 admitted to the ICU.

scholarly journals The Autophagy Pathway: A Critical Route in the Disposal of Alpha 1-Antitrypsin Aggregates That Holds Many Mysteries

2021 ◽  
Vol 22 (4) ◽  
pp. 1875
Author(s):  
Celine Leon ◽  
Marion Bouchecareilh
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Therapeutic Option ◽  
Ubiquitin Proteasome System ◽  
Therapeutic Benefit ◽  
Cellular Functions ◽  
Precise Control ◽  
New Therapeutic Approaches ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

The maintenance of proteome homeostasis, or proteostasis, is crucial for preserving cellular functions and for cellular adaptation to environmental challenges and changes in physiological conditions. The capacity of cells to maintain proteostasis requires precise control and coordination of protein synthesis, folding, conformational maintenance, and clearance. Thus, protein degradation by the ubiquitin–proteasome system (UPS) or the autophagy–lysosomal system plays an essential role in cellular functions. However, failure of the UPS or the autophagic process can lead to the development of various diseases (aging-associated diseases, cancer), thus both these pathways have become attractive targets in the treatment of protein conformational diseases, such as alpha 1-antitrypsin deficiency (AATD). The Z alpha 1-antitrypsin (Z-AAT) misfolded variant of the serine protease alpha 1-antitrypsin (AAT) is caused by a structural change that predisposes it to protein aggregation and dramatic accumulation in the form of inclusion bodies within liver hepatocytes. This can lead to clinically significant liver disease requiring liver transplantation in childhood or adulthood. Treatment of mice with autophagy enhancers was found to reduce hepatic Z-AAT aggregate levels and protect them from AATD hepatotoxicity. To date, liver transplantation is the only curative therapeutic option for patients with AATD-mediated liver disease. Therefore, the development and discovery of new therapeutic approaches to delay or overcome disease progression is a top priority. Herein, we review AATD-mediated liver disease and the overall process of autophagy. We highlight the role of this system in the regulation of Z-variant degradation and its implication in AATD-medicated liver disease, including some open questions that remain challenges in the field and require further elucidation. Finally, we discuss how manipulation of autophagy could provide multiple routes of therapeutic benefit in AATD-mediated liver disease.

scholarly journals RIPK3-Mediated Necroptosis and Neutrophil Infiltration Are Associated with Poor Prognosis in Patients with Alcoholic Cirrhosis

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Zhenzhen Zhang ◽  
Guomin Xie ◽  
Li Liang ◽  
Hui Liu ◽  
Jing Pan ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Poor Prognosis ◽  
Alcoholic Cirrhosis ◽  
Normal Liver ◽  
Neutrophil Infiltration ◽  
Meld Score ◽  
End Stage Liver Disease ◽  
Cirrhotic Patients ◽  
End Stage

Alcoholic cirrhosis is an end-stage liver disease with impaired survival and often requires liver transplantation. Recent data suggests that receptor-interacting protein kinase-3- (RIPK3-) mediated necroptosis plays an important role in alcoholic cirrhosis. Additionally, neutrophil infiltration is the most characteristic pathologic hallmark of alcoholic hepatitis. Whether RIPK3 level is correlated with neutrophil infiltration or poor prognosis in alcoholic cirrhotic patients is still unknown. We aimed to determine the correlation of RIPK3 and neutrophil infiltration with the prognosis in the end-stage alcoholic cirrhotic patients. A total of 20 alcoholic cirrhotic patients subjected to liver transplantation and 5 normal liver samples from control patients were retrospectively enrolled in this study. Neutrophil infiltration and necroptosis were assessed by immunohistochemical staining for myeloperoxidase (MPO) and RIPK3, respectively. The noninvasive score system (model for end-stage liver disease (MELD)) and histological score systems (Ishak, Knodell, and ALD grading and ALD stage) were used to evaluate the prognosis. Neutrophil infiltration was aggravated in patients with a high MELD score (≥32) in the liver. The MPO and RIPK3 levels in the liver were positively related to the Ishak score. The RIPK3 was also significantly and positively related to the Knodell score. In conclusion, RIPK3-mediated necroptosis and neutrophil-mediated alcoholic liver inflammatory response are highly correlated with poor prognosis in patients with end-stage alcoholic cirrhosis. RIPK3 and MPO might serve as potential predictors for poor prognosis in alcoholic cirrhotic patients.

scholarly journals Management of chronic hepatitis B before and after liver transplantation

2017 ◽  
Vol 9 (1) ◽  
pp. 79-84 ◽  
Author(s):  
B Wang ◽  
K Agarwal ◽  
D Joshi
Keyword(s):  
Liver Transplantation ◽  
Chronic Hepatitis ◽  
Liver Disease ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Public Health Problem ◽  
Global Public Health ◽  
Chronic Hepatitis B Infection ◽  
Before And After ◽  
Related Liver Disease

Chronic hepatitis B infection is a global public health problem associated with significant morbidity and mortality. Persistent infection may evolve to liver cirrhosis and hepatocellular carcinoma, and hepatitis B-related liver disease is a common indication for liver transplantation. Patients with advanced liver disease should be treated with antiviral therapy which may result in clinical improvement. The management of patients after liver transplant then focuses on preventing hepatitis B recurrence in the graft. With the introduction of prophylactic treatment, patient and graft survival has improved significantly. In this review, we will discuss the management of patients with hepatitis B-related cirrhosis, both compensated and decompensated. We also review the management of hepatitis B after liver transplantation.

scholarly journals Role of acute phase proteins in diagnosis of uremic pancreatitis and destructive pancreatitis in patients receiving renal replacement therapy (programmed hemodialysis)

2021 ◽  
Vol 38 (5) ◽  
pp. 115-122
Author(s):  
Kazim G. Gasanov ◽  
Viktor A. Zurnadzhyants ◽  
Eldar A. Kchibekov ◽  
M. I. Shikhragimov
Keyword(s):  
Renal Replacement Therapy ◽  
Serum Concentration ◽  
Blood Serum ◽  
Replacement Therapy ◽  
Acute Phase Proteins ◽  
Control Group ◽  
Serum Concentrations ◽  
High Concentration ◽  
Surgical Unit

Objective. To determine the blood serum 2-microglobulin and 2-macroglobulin concentration in patients undergoing renal replacement therapy (programmed hemodialysis) for the diagnosis of uremic pancreatitis and / or destructive pancreatitis. Materials and methods. The study involved 52 patients admitted to the Surgical Unit of Astrakhan "RZhD-Medicine" Hospital and City Clinical Hospital № 3. The blood serum 2-microglobulin and 2-macroglobulin concentration was analyzed in patients admitted on an emergency basis with suspicion of uremic pancreatitis and destructive pancreatitis, who receive renal replacement therapy (programmed hemodialysis). The control group included 50 outpatients undergoing renal replacement therapy (programmed hemodialysis). The study did not include patients with suspected pancreatitis who were not receiving renal replacement therapy. The period of the study is 20192021. Results. The concentration of blood serum 2-microglobulin is statistically higher than normal in all patients, who had received renal replacement therapy (programmed hemodialysis) in anamnesis. The most statistically high concentration of 2-microglobulin was revealed while studying patients with uremic pancreatitis (n = 34), and was (30.0 2.75 mg/l) compared with the blood serum concentration in patients with destructive pancreatitis (8 0.51 mg / l). The concentration of 2-macroglobulin was statistically lower in destructive pancreatitis (n = 18) and was 615 161 mg/l compared with uremic pancreatitis (980 216 mg/l). In the control group of outpatients (n = 50) receiving renal replacement therapy (programmed hemodialysis), no statistically significant blood serum concentrations of 2-microglobulin and 2-macroglobulin were found. Conclusions. A clear dependence of the concentration of 2-microglobulin and 2-macroglobulin on the severity of uremic pancreatitis and destructive pancreatitis was established. Statistically high values of 2-microglobulin concentrations were obtained in patients with uremic pancreatitis, and the 2-macroglobulin level was statistically low in destructive pancreatitis.

Role of IFN-λs ,IFN-λs related genes and the DEPDC5 gene in Hepatitis B virus-related liver disease

2014 ◽  
Vol 21 (7) ◽  
pp. e29-e38 ◽  
Author(s):  
N. Ma ◽  
X. Zhang ◽  
F. Yu ◽  
P. Gao ◽  
Q. Fan ◽  
...  
Keyword(s):  
Liver Disease ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
B Virus ◽  
Related Liver Disease
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