BACKGROUND 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 m...BACKGROUND 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.AIM To evaluate the impact of clinical parameters and AATD phenotypes,particularly the Pi*Z allele,in liver fibrosis.METHODS Cross-sectional cohort study including consecutive patients with AATD followed in Pulmonology or Hepatology consultation.RESULTS 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).CONCLUSION 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.展开更多
AIM:To evaluate the association between alpha-1 antitrypsin deficiency(A1ATD) and hepatocellular carcinoma(HCC) in patients with end-stage liver disease(ESLD).METHODS:Patients with cirrhosis and ESLD referred to the C...AIM:To evaluate the association between alpha-1 antitrypsin deficiency(A1ATD) and hepatocellular carcinoma(HCC) in patients with end-stage liver disease(ESLD).METHODS:Patients with cirrhosis and ESLD referred to the Cleveland Clinic Foundation for liver transplantation between 2003 and 2014 were included in the study(N = 675). ESLD was defined as having histological features of cirrhosis and/or radiological evidence of cirrhosis in the context of portal hypertension(ascites,variceal bleeding,thrombocytopenia,or hepatic encephalopathy). A1 ATD was diagnosed using phenotype characterization(MZ or ZZ),liver biopsy detection of PAS-positive diastaseresistant(PAS+) globules,or both. Patients with other causes of liver diseases such as hepatitis C virus(HCV),alcoholic liver disease and non-alcoholic steatohepatitis(NASH) or NASH were also included in the study. HCC was diagnosed by using imaging modalities,biopsy findings,or explanted liver inspection. Follow-up time was defined as the number of years from the diagnosis of cirrhosis to the diagnosis of hepatocellular carcinoma,or from the diagnosis of cirrhosis to the last follow up visit. The rate of HCC was assessed using time-tointerval analysis for interval censored data.RESULTS:This study included 675 patients. 7% of subjects had A1ATD(n = 47). Out of all subjects who did not have A1 ATD,46% had HCV,17% had alcoholic liver disease,19% had NASH and 18% had another primary diagnosis. Of the 47 subjects with A1 ATD,15 had a primary diagnosis of A1ATD(PI*ZZ phenotype and PAS+ globules),8 had a PI*MZ phenotype alone,14 had PAS+ alone,and 10 had both the PI*MZ phenotype and PAS+. Median follow-up time was 3.4(25th,75 th percentiles:1,5.2) years. The overall rate of hepatocellular carcinoma in all subjects was 29%(n = 199). In the A1 ATD group,the incidence rate of HCC was 8.5% compared to 31% in the group of patients with other causes of cirrhosis(P = 0.001). Patients with ESLD due to A1 ATD had the lowest yearly cumulative rate of hepatocellular carcinoma at 0.88% per year compared to 2.7% for those with HCV cirrhosis,1.5% in patients with NASH and 0.9% in alcohol-induced liver disease(P < 0.001).CONCLUSION:Within this group of patients with ESLD,there was no significant association between A1 ATD and increased risk of HCC.展开更多
Post-hepatectomy liver failure(PHLF) is a leading cause of morbidity and mortality following major liver resection. The development of PHLF is dependent on the volume of the remaining liver tissue and hepatocyte funct...Post-hepatectomy liver failure(PHLF) is a leading cause of morbidity and mortality following major liver resection. The development of PHLF is dependent on the volume of the remaining liver tissue and hepatocyte function. Without effective pre-operative assessment, patients with undiagnosed liver disease could be at increased risk of PHLF. We report a case of a 60-year-old male patient with PHLF secondary to undiagnosed alpha-1-antitrypsin deficiency(AATD) following major liver resection. He initially presented with acute large bowel obstruction secondary to a colorectal adenocarcinoma, which had metastasized to the liver. There was no significant past medical history apart from mild chronic obstructive pulmonary disease. After colonic surgery and liver directed neo-adjuvant chemotherapy, he underwent a laparoscopic partially extended right hepatectomy and radio-frequency ablation. Post-operatively he developed PHLF. The cause of PHLF remained unknown, prompting reanalysis of the histology, which showed evidence of AATD. He subsequently developed progressive liver dysfunction, portal hypertension, and eventually an extensive parastomal bleed, which led to his death; this was ultimately due to a combination of AATD and chemotherapy. This case highlights that formal testing for AATD in all patients with a known history of chronic obstructive pulmonary disease, heavy smoking, or strong family history could help prevent the development of PHLF in patients undergoing major liver resection.展开更多
The serine proteinase inhibitor α-1 antitrypsin(AAT) is produced principally by the liver at the rate of 2 g/d.It is secreted into the circulation and provides an antiprotease protective screen throughout the body bu...The serine proteinase inhibitor α-1 antitrypsin(AAT) is produced principally by the liver at the rate of 2 g/d.It is secreted into the circulation and provides an antiprotease protective screen throughout the body but most importantly in the lung,where it can neutralise the activity of the serine protease neutrophil elastase.Mutations leading to def iciency in AAT are associated with liver and lung disease.The most notable is the Z AAT mutation,which encodes a misfolded variant of the AAT protein in which the glutamic acid at position 342 is replaced by a lysine.More than 95% of all individuals with AAT def iciency carry at least one Z allele.ZAAT protein is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum(ER) of hepatocytes and other AAT-producing cells.This results in a loss of function associated with decreased circulating and intrapulmonary levels of AAT.However,the misfolded protein acquires a toxic gain of function that impacts on the ER.A major function of the ER is to ensure correct protein folding.ZAAT interferes with this function and promotes ER stress responses and inflammation.Here the signalling pathways activated during ER stress in response to accumulation of ZAAT are described and therapeutic strategies that can potentially relieve ER stress are discussed.展开更多
Alpha1-antitrypsin deficiency is an autosomal recessive disease characterized by reduced serum levels of alpha1-antitrypsin(AAT)due to mutations in the SERPINA1 gene causing early onset pulmonary emphysema and,occasio...Alpha1-antitrypsin deficiency is an autosomal recessive disease characterized by reduced serum levels of alpha1-antitrypsin(AAT)due to mutations in the SERPINA1 gene causing early onset pulmonary emphysema and,occasionally,chronic liver disease.We report an incidental finding of a novel null AAT allele,Q0Milano,consisting of a 17 nucleotides deletion in exon 3 of SERPINA1 gene,in an Italian child with persistently increased liver enzymes,a mild decrease in circulating AAT levels and without any pulmonary disease.Q0Milano variant results in an unfunctional protein lacking of AAT active site,as the resultant protein is truncated near PiS locus involved in AAT protein stability.展开更多
AIM To systematically review literature for management of alpha-1 antitrypsin deficiency(AATD) panniculitis. METHODS Multiple databases were searched using combinations of pertinent terms. Articles were selected descr...AIM To systematically review literature for management of alpha-1 antitrypsin deficiency(AATD) panniculitis. METHODS Multiple databases were searched using combinations of pertinent terms. Articles were selected describing panniculitis treatment in patients with AAT < 11 μmol and/or PiZZ genotype, with no language limitation. All relevant articles were accessed in full text. Independent review of abstracts and full manuscripts was conducted by 2 reviewers, and quality assessment by one reviewer(checked by a second). Data extraction was conducted byone reviewer(checked by a second). Narrative synthesis only was conducted, as data were unsuitable for metaanalysis.RESULTS Thirty-two case reports and 4 case series were found. Augmentation therapy(infusions of plasma-derived AAT) was the most successful, with complete resolution of symptoms in all patients. Dapsone is a less expensive option, and it achieved clinical resolution in 62% of patients, but it is very poorly tolerated. Among other single-agent antibiotics, doxycycline was the most successful with complete clinical resolution seen in 33% of patients. Immunosuppressants were largely unsuccessful; 80% of patients exhibited no response. Liver transplantation and therapeutic plasma exchange displayed complete resolution in 66% of patients. Other strategies, such as non-steroidal anti-inflammatory drugs or antibiotics other than dapsone did not show sufficient response rates to recommend their use. Authors note the risk of bias imposed by the type of evidence(case reports, case series) available in this field.CONCLUSION Dapsone is the recommended first line therapy for AATD panniculitis, followed by augmentation therapy. Plasma exchange may be an alternative in the setting of rapidly progressive disease.展开更多
According to the latest World Health Organization report 64 million people suffer from Chronic Obstructive Pulmonary Disease （COPD）, 3 million people died from COPD and it is predicted that COPD will become the thir...According to the latest World Health Organization report 64 million people suffer from Chronic Obstructive Pulmonary Disease （COPD）, 3 million people died from COPD and it is predicted that COPD will become the third leading cause of death worldwide by 2030. The alpha-1 antitrypsin deficiency is a rarely diagnosed hereditary disease caused by a genetic mutation and it is one of the most prevalent genetic disorders primarily affecting the lungs, especially in the form of COPD or emphysema, but in some cases also the liver or skin. The Global Initiative for Chronic Obstructive Lung Disease recommends all patients with COPD at a young age or significant family history to be examined for alpha-1 antitrypsin deficiency. This article presents the case of a 42 year old, female patient, Portuguese, with history of Chronic Obstructive Pulmonary Disease, 40 pack units/year smoker, with unknown family history, coming to her family doctor with breath shortness, especially during physical activities, with unsatisfying response to pharmacological prescribed therapy. Physical examination was normal. Alpha- 1 antitrypsin deficiency was confirmed by blood testing. All patient＇s first degree relatives were investigated showing low alpha-1 antitrypsin blood concentrations thus genetic tests were later performed. This case reinforces the need for primary care physicians to be aware of alphal-antitrypsin deficit as an underdiagnosed clinical entity.展开更多
Background and Aims:Alpha-1 antitrypsin deficiency(AATD)is a genetic disorder characterized by the misfolding and accumulation of the mutant variant of alpha-1 antitrypsin(AAT)within hepatocytes,which limits its acces...Background and Aims:Alpha-1 antitrypsin deficiency(AATD)is a genetic disorder characterized by the misfolding and accumulation of the mutant variant of alpha-1 antitrypsin(AAT)within hepatocytes,which limits its access to the circulation and exposes the lungs to protease-mediated tissue damage.This results in progressive liver disease secondary to AAT polymerization and accumulation,and chronic obstructive pulmonary disease(COPD)due to deficient levels of AAT within the lungs.Our goal was to characterize the unique effects of COPD secondary to AATD on liver disease and gene expression.Methods:A subcohort of AATD individuals with COPD(n=33)and AATD individuals without COPD(n=14)were evaluated in this study from our previously reported cross-sectional cohort.We used immunohistochemistry to assess the AATD liver phenotype,and RNA sequencing to explore liver transcriptomics.We observed a distinct transcriptomic profile in liver tissues from AATD individuals with COPD compared to those without.Results:A total of 339 genes were differentially expressed.Canonical pathways related to fibrosis,extracellular matrix remodeling,collagen deposition,hepatocellular damage,and inflammation were significantly upregulated in the livers of AATD individuals with COPD.Histopathological analysis also revealed higher levels of fibrosis and hepatocellular damage in these individuals.Conclusions:Our data supports a relationship between the development of COPD and liver disease in AATD and introduces genes and pathways that may play a role in AATD liver disease when COPD is present.We believe addressing lung impairment and airway inflammation may be an approach to managing AATD-related liver disease.展开更多
Community-acquired pneumonia(CAP)poses a significant global health threat,particularly affecting vulnerable populations.Biomarkers and scoring systems play a crucial role in diagnosing,assessing severity,and guiding t...Community-acquired pneumonia(CAP)poses a significant global health threat,particularly affecting vulnerable populations.Biomarkers and scoring systems play a crucial role in diagnosing,assessing severity,and guiding treatment decisions for CAP patients.Biomarkers like C reactive protein,procalcitonin,and the neutrophil-to-lymphocyte ratio aid in diagnosis and severity assessment,while scoring systems such as CURB-65 and Pneumonia Severity Index classify patients into risk categories.Emerging biomarkers(uremia,elevated respiratory rate,hypotension,and age≥65)like serum amyloid A and S100 proteins show promise in predicting disease severity and prognosis.However,further research is needed to determine their precise roles and clinical utility in CAP management.展开更多
Objective To investigate whether pretreatment with α1,-antitrypsin (AAT) can attenuate acute lung injury (ALI) in rabbits induced with endotoxin.Methods Thirty-two healthy adult New Zealand rabbits were anaesthetized...Objective To investigate whether pretreatment with α1,-antitrypsin (AAT) can attenuate acute lung injury (ALI) in rabbits induced with endotoxin.Methods Thirty-two healthy adult New Zealand rabbits were anaesthetized, tracheotomized and mechanically ventilated. They were then randomly divided into four groups (n =8): (1) Infusion of Escherichia coli endotoxin [ Lipopolysaccharide (LPS) 500μg/kg ] without AAT (Group LPS). (2) Infusion of AAT 120 mg/kg at 15 minutes after LPS (Group LAV). (3) Infusion of AAT 120 mg/kg without endotoxin (Group AAT). (4) Infusion of saline 4 ml/kg as control (Group NS). Arterial blood gases, peripheral leukocyte counts and airway pressure were recorded every hour for eight hours. Physiologic intrapulmonary shunting (Qs/Qt) was measured every four hours. After eight hours, blood samples were collected for measurement of plasma concentration and activity of AAT. Then, the animals were sacrificed, and bronchoalveolar lavage fluid (BALF) was collected for measurement of concentrations of total protein (TP), interleukin-8 (IL-8), tumor necrosis factor (TNFa, the activities of NE and AAT, total phospholipids (TPL) and disaturated phosphatidylcholine (DSPC). In addition, the wet-to-dry lung weight ratio (W/D) was measured.Results The infusion of endotoxin induced decreases in arterial oxygen pressure (PaO2), peripheral leukocyte counts, total respiratory compliance (TLC) and the increases in peak pressure (Ppeak), Qs/ Qt compared with the baseline values ( P < 0. 05). The increased plasma concentration but reduced activity of AAT was also found in contrast to that in Group NS (P<0. 05). In the BALF, the activity of AAT, TPL, DSPC/TPL were lower than those in Group NS (P<0. 05), but the concentrations of albumin, IL-8, TNFα, the activity of NE and the ratio of W/D were higher than those in Group NS (P <0. 05). The pretreatment of AAT attenuated the deterioration of oxygenation, the reduction of compliance and the deterioration of other physiological and biochemical parameters mentioned above.Conclusion Pretreatment with AAT could attenuate endotoxin-induced lung injury in rabbits. Those beneficial effects of AAT might be due, in part, to reduction in the levels of mediators that could activate neutrophils, in addition to the direct inhibitory effect on neutrophil elastase.展开更多
Background： Previous studies conducted in various geographical and ethnical populations have shown that Alpha-1 -antitrypsin （Alpha-1-AT） expression affects the occurrence and progression of chronic obstructive puh...Background： Previous studies conducted in various geographical and ethnical populations have shown that Alpha-1 -antitrypsin （Alpha-1-AT） expression affects the occurrence and progression of chronic obstructive puh-nonary disease （COPD）. We aimed to explore the associations of rs9944155AG, rsl051052AG, and rs1243166AG polymorphisms in the A lpha-1-A T gene with the risk of COPD in Uygur population in the Kashgar region. Methods： From March 2013 to December 2015. a total of 225 Uygur COPD patients and 198 healthy people were recruited as cases and controls, respectively, in Kashgar region. DNA was extracted according to the protocol of the DNA genome kit, and Sequenom MassARRAY single-nucleotide polymorphism technology was used for genotype determination. Serum concentration of Alpha-1-AT was detected by enzyme-linked immunosorbent assay. A logistic regression model was used to estimate the associations of polymorphisms with COPD. Results： The rs1243166-G allele was associated with a higher risk of COPD （odds ratio [OR] = 2.039, 95% confidence interval [CI]： 1.116-3.725, P = 0.019）. In cases, Alpha-1-AT levels were the highest among participants can-yiug rs1243166 AG genotype, followed by AA and GG genotype （χ2 = 11.89, P = 0.003）. Similarly, the rs1051052-G allele was associated with a higher risk of COPD （OR = 19.433, 95% CI： 8.783-43.00, P 〈 0.001）. The highest Alpha-1-ATlevels were observed in cases carrying rs1051052 AA genotype, followed by cases with AG and GG genotypes （χ2= 122.45, P 〈 0.001）. However, individuals with rs9944155-G allele exhibited a lower risk of COPD than those carrying the rs9944155-A allele （OR = 0.121, 95% CI： 0.070-0.209, P 〈 0.001 ）. in both cases and controls, no significant difference in Alpha-l-AT levels was observed among various rs9944115 genotypes. Conclusions： rs 1243166, rs9944155, and rs 1051052 sites of Alpha- I-A Tmay be associated with the COPD morbidity in Uygur population. While rs 1243166-G allele and rs1051052-G allele are associated with an increased risk of developing COPD, rs9944155-G allele is a protect locus in Uygur population. Alpha1-AT levels in Uygur COPD patients were lower than those in healthy people and differed among patients with different rs 1051052 AG and rs 1243166 AG genotypes.展开更多
目的探讨苏黄止咳胶囊联合福多司坦片治疗支气管扩张对患者血清肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、α1-抗胰蛋白酶(α1-antitryp sin,α1-AT)、白细胞介素-37(interleukin-37,IL-37)水平的影响。方法选取支气管扩张患...目的探讨苏黄止咳胶囊联合福多司坦片治疗支气管扩张对患者血清肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、α1-抗胰蛋白酶(α1-antitryp sin,α1-AT)、白细胞介素-37(interleukin-37,IL-37)水平的影响。方法选取支气管扩张患者63例,用随机数字表法分为观察组(n=32)和对照组(n=31)。对照组采用福多司坦片治疗,观察组在对照组治疗的基础上联合苏黄止咳胶囊。比较2组患者的治疗疗效、中医证候积分、肺功能指标、TNF-α、α1-AT、IL-37、呼吸状况和不良反应。结果治疗后,观察组的总有效率(96.88%)高于对照组(80.65%),P<0.05;观察组的中医证候积分低于对照组,P<0.05;观察组的第1秒用力呼气容积(forced expiratory volume in one second,FEV1)、用力肺活量(forced vital capacity,FVC)、一氧化碳弥散量占预计值百分比(carbon monoxide diffusion capacity as a percentage of predicted value,DLCO%pred)均高于对照组,P<0.05;观察组的IL-37水平高于对照组,P<0.05,观察组的TNF-α、α1-AT水平低于对照组,P<0.05;观察组的圣乔治呼吸问卷(St.George’s respiratory questionnaire,SGRQ)各维度评分均低于对照组,P<0.05;观察组不良反应发生率低于对照组,P<0.05。结论采用苏黄止咳胶囊联合福多司坦片治疗支气管扩张能有效提高患者的治疗疗效,改善其中医证候,改善TNF-α、α1-AT、IL-37水平、肺功能指标和呼吸功能。展开更多
BACKGROUND Alpha-1 antitrypsin deficiency is a rare genetic disease and a leading cause of inherited alterations in plasma protein metabolism(APPM).AIM To understand the prevalence,burden and progression of liver dise...BACKGROUND Alpha-1 antitrypsin deficiency is a rare genetic disease and a leading cause of inherited alterations in plasma protein metabolism(APPM).AIM To understand the prevalence,burden and progression of liver disease in patients with APPM including alpha-1 antitrypsin deficiency.METHODS 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.RESULTS 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%).CONCLUSION Among patients with liver disease,those with APPM experience substantial burden and earlier liver disease progression than patients without APPM.展开更多
文摘BACKGROUND 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.AIM To evaluate the impact of clinical parameters and AATD phenotypes,particularly the Pi*Z allele,in liver fibrosis.METHODS Cross-sectional cohort study including consecutive patients with AATD followed in Pulmonology or Hepatology consultation.RESULTS 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).CONCLUSION 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.
文摘AIM:To evaluate the association between alpha-1 antitrypsin deficiency(A1ATD) and hepatocellular carcinoma(HCC) in patients with end-stage liver disease(ESLD).METHODS:Patients with cirrhosis and ESLD referred to the Cleveland Clinic Foundation for liver transplantation between 2003 and 2014 were included in the study(N = 675). ESLD was defined as having histological features of cirrhosis and/or radiological evidence of cirrhosis in the context of portal hypertension(ascites,variceal bleeding,thrombocytopenia,or hepatic encephalopathy). A1 ATD was diagnosed using phenotype characterization(MZ or ZZ),liver biopsy detection of PAS-positive diastaseresistant(PAS+) globules,or both. Patients with other causes of liver diseases such as hepatitis C virus(HCV),alcoholic liver disease and non-alcoholic steatohepatitis(NASH) or NASH were also included in the study. HCC was diagnosed by using imaging modalities,biopsy findings,or explanted liver inspection. Follow-up time was defined as the number of years from the diagnosis of cirrhosis to the diagnosis of hepatocellular carcinoma,or from the diagnosis of cirrhosis to the last follow up visit. The rate of HCC was assessed using time-tointerval analysis for interval censored data.RESULTS:This study included 675 patients. 7% of subjects had A1ATD(n = 47). Out of all subjects who did not have A1 ATD,46% had HCV,17% had alcoholic liver disease,19% had NASH and 18% had another primary diagnosis. Of the 47 subjects with A1 ATD,15 had a primary diagnosis of A1ATD(PI*ZZ phenotype and PAS+ globules),8 had a PI*MZ phenotype alone,14 had PAS+ alone,and 10 had both the PI*MZ phenotype and PAS+. Median follow-up time was 3.4(25th,75 th percentiles:1,5.2) years. The overall rate of hepatocellular carcinoma in all subjects was 29%(n = 199). In the A1 ATD group,the incidence rate of HCC was 8.5% compared to 31% in the group of patients with other causes of cirrhosis(P = 0.001). Patients with ESLD due to A1 ATD had the lowest yearly cumulative rate of hepatocellular carcinoma at 0.88% per year compared to 2.7% for those with HCV cirrhosis,1.5% in patients with NASH and 0.9% in alcohol-induced liver disease(P < 0.001).CONCLUSION:Within this group of patients with ESLD,there was no significant association between A1 ATD and increased risk of HCC.
文摘Post-hepatectomy liver failure(PHLF) is a leading cause of morbidity and mortality following major liver resection. The development of PHLF is dependent on the volume of the remaining liver tissue and hepatocyte function. Without effective pre-operative assessment, patients with undiagnosed liver disease could be at increased risk of PHLF. We report a case of a 60-year-old male patient with PHLF secondary to undiagnosed alpha-1-antitrypsin deficiency(AATD) following major liver resection. He initially presented with acute large bowel obstruction secondary to a colorectal adenocarcinoma, which had metastasized to the liver. There was no significant past medical history apart from mild chronic obstructive pulmonary disease. After colonic surgery and liver directed neo-adjuvant chemotherapy, he underwent a laparoscopic partially extended right hepatectomy and radio-frequency ablation. Post-operatively he developed PHLF. The cause of PHLF remained unknown, prompting reanalysis of the histology, which showed evidence of AATD. He subsequently developed progressive liver dysfunction, portal hypertension, and eventually an extensive parastomal bleed, which led to his death; this was ultimately due to a combination of AATD and chemotherapy. This case highlights that formal testing for AATD in all patients with a known history of chronic obstructive pulmonary disease, heavy smoking, or strong family history could help prevent the development of PHLF in patients undergoing major liver resection.
基金Supported by The U.S. Alpha One Foundation,the Health Research Board of Ireland,the Medical Research Charities Group,the Programmes for Research in Third Level Institutes administered by the Higher Education Authority and the Children’s Medical and Research Centre,Crumlin Hospital
文摘The serine proteinase inhibitor α-1 antitrypsin(AAT) is produced principally by the liver at the rate of 2 g/d.It is secreted into the circulation and provides an antiprotease protective screen throughout the body but most importantly in the lung,where it can neutralise the activity of the serine protease neutrophil elastase.Mutations leading to def iciency in AAT are associated with liver and lung disease.The most notable is the Z AAT mutation,which encodes a misfolded variant of the AAT protein in which the glutamic acid at position 342 is replaced by a lysine.More than 95% of all individuals with AAT def iciency carry at least one Z allele.ZAAT protein is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum(ER) of hepatocytes and other AAT-producing cells.This results in a loss of function associated with decreased circulating and intrapulmonary levels of AAT.However,the misfolded protein acquires a toxic gain of function that impacts on the ER.A major function of the ER is to ensure correct protein folding.ZAAT interferes with this function and promotes ER stress responses and inflammation.Here the signalling pathways activated during ER stress in response to accumulation of ZAAT are described and therapeutic strategies that can potentially relieve ER stress are discussed.
基金Supported by The Borsa M.Coppo AISF,Italian Association for the Study of the Liver to Rametta R
文摘Alpha1-antitrypsin deficiency is an autosomal recessive disease characterized by reduced serum levels of alpha1-antitrypsin(AAT)due to mutations in the SERPINA1 gene causing early onset pulmonary emphysema and,occasionally,chronic liver disease.We report an incidental finding of a novel null AAT allele,Q0Milano,consisting of a 17 nucleotides deletion in exon 3 of SERPINA1 gene,in an Italian child with persistently increased liver enzymes,a mild decrease in circulating AAT levels and without any pulmonary disease.Q0Milano variant results in an unfunctional protein lacking of AAT active site,as the resultant protein is truncated near PiS locus involved in AAT protein stability.
文摘AIM To systematically review literature for management of alpha-1 antitrypsin deficiency(AATD) panniculitis. METHODS Multiple databases were searched using combinations of pertinent terms. Articles were selected describing panniculitis treatment in patients with AAT < 11 μmol and/or PiZZ genotype, with no language limitation. All relevant articles were accessed in full text. Independent review of abstracts and full manuscripts was conducted by 2 reviewers, and quality assessment by one reviewer(checked by a second). Data extraction was conducted byone reviewer(checked by a second). Narrative synthesis only was conducted, as data were unsuitable for metaanalysis.RESULTS Thirty-two case reports and 4 case series were found. Augmentation therapy(infusions of plasma-derived AAT) was the most successful, with complete resolution of symptoms in all patients. Dapsone is a less expensive option, and it achieved clinical resolution in 62% of patients, but it is very poorly tolerated. Among other single-agent antibiotics, doxycycline was the most successful with complete clinical resolution seen in 33% of patients. Immunosuppressants were largely unsuccessful; 80% of patients exhibited no response. Liver transplantation and therapeutic plasma exchange displayed complete resolution in 66% of patients. Other strategies, such as non-steroidal anti-inflammatory drugs or antibiotics other than dapsone did not show sufficient response rates to recommend their use. Authors note the risk of bias imposed by the type of evidence(case reports, case series) available in this field.CONCLUSION Dapsone is the recommended first line therapy for AATD panniculitis, followed by augmentation therapy. Plasma exchange may be an alternative in the setting of rapidly progressive disease.
文摘According to the latest World Health Organization report 64 million people suffer from Chronic Obstructive Pulmonary Disease （COPD）, 3 million people died from COPD and it is predicted that COPD will become the third leading cause of death worldwide by 2030. The alpha-1 antitrypsin deficiency is a rarely diagnosed hereditary disease caused by a genetic mutation and it is one of the most prevalent genetic disorders primarily affecting the lungs, especially in the form of COPD or emphysema, but in some cases also the liver or skin. The Global Initiative for Chronic Obstructive Lung Disease recommends all patients with COPD at a young age or significant family history to be examined for alpha-1 antitrypsin deficiency. This article presents the case of a 42 year old, female patient, Portuguese, with history of Chronic Obstructive Pulmonary Disease, 40 pack units/year smoker, with unknown family history, coming to her family doctor with breath shortness, especially during physical activities, with unsatisfying response to pharmacological prescribed therapy. Physical examination was normal. Alpha- 1 antitrypsin deficiency was confirmed by blood testing. All patient＇s first degree relatives were investigated showing low alpha-1 antitrypsin blood concentrations thus genetic tests were later performed. This case reinforces the need for primary care physicians to be aware of alphal-antitrypsin deficit as an underdiagnosed clinical entity.
基金sponsored by a grant from the Alpha-1 Foundation(AGR00019116).
文摘Background and Aims:Alpha-1 antitrypsin deficiency(AATD)is a genetic disorder characterized by the misfolding and accumulation of the mutant variant of alpha-1 antitrypsin(AAT)within hepatocytes,which limits its access to the circulation and exposes the lungs to protease-mediated tissue damage.This results in progressive liver disease secondary to AAT polymerization and accumulation,and chronic obstructive pulmonary disease(COPD)due to deficient levels of AAT within the lungs.Our goal was to characterize the unique effects of COPD secondary to AATD on liver disease and gene expression.Methods:A subcohort of AATD individuals with COPD(n=33)and AATD individuals without COPD(n=14)were evaluated in this study from our previously reported cross-sectional cohort.We used immunohistochemistry to assess the AATD liver phenotype,and RNA sequencing to explore liver transcriptomics.We observed a distinct transcriptomic profile in liver tissues from AATD individuals with COPD compared to those without.Results:A total of 339 genes were differentially expressed.Canonical pathways related to fibrosis,extracellular matrix remodeling,collagen deposition,hepatocellular damage,and inflammation were significantly upregulated in the livers of AATD individuals with COPD.Histopathological analysis also revealed higher levels of fibrosis and hepatocellular damage in these individuals.Conclusions:Our data supports a relationship between the development of COPD and liver disease in AATD and introduces genes and pathways that may play a role in AATD liver disease when COPD is present.We believe addressing lung impairment and airway inflammation may be an approach to managing AATD-related liver disease.
文摘Community-acquired pneumonia(CAP)poses a significant global health threat,particularly affecting vulnerable populations.Biomarkers and scoring systems play a crucial role in diagnosing,assessing severity,and guiding treatment decisions for CAP patients.Biomarkers like C reactive protein,procalcitonin,and the neutrophil-to-lymphocyte ratio aid in diagnosis and severity assessment,while scoring systems such as CURB-65 and Pneumonia Severity Index classify patients into risk categories.Emerging biomarkers(uremia,elevated respiratory rate,hypotension,and age≥65)like serum amyloid A and S100 proteins show promise in predicting disease severity and prognosis.However,further research is needed to determine their precise roles and clinical utility in CAP management.
基金the Scientific Foundation of the Ministry of Health (No: 98-1-150)
文摘Objective To investigate whether pretreatment with α1,-antitrypsin (AAT) can attenuate acute lung injury (ALI) in rabbits induced with endotoxin.Methods Thirty-two healthy adult New Zealand rabbits were anaesthetized, tracheotomized and mechanically ventilated. They were then randomly divided into four groups (n =8): (1) Infusion of Escherichia coli endotoxin [ Lipopolysaccharide (LPS) 500μg/kg ] without AAT (Group LPS). (2) Infusion of AAT 120 mg/kg at 15 minutes after LPS (Group LAV). (3) Infusion of AAT 120 mg/kg without endotoxin (Group AAT). (4) Infusion of saline 4 ml/kg as control (Group NS). Arterial blood gases, peripheral leukocyte counts and airway pressure were recorded every hour for eight hours. Physiologic intrapulmonary shunting (Qs/Qt) was measured every four hours. After eight hours, blood samples were collected for measurement of plasma concentration and activity of AAT. Then, the animals were sacrificed, and bronchoalveolar lavage fluid (BALF) was collected for measurement of concentrations of total protein (TP), interleukin-8 (IL-8), tumor necrosis factor (TNFa, the activities of NE and AAT, total phospholipids (TPL) and disaturated phosphatidylcholine (DSPC). In addition, the wet-to-dry lung weight ratio (W/D) was measured.Results The infusion of endotoxin induced decreases in arterial oxygen pressure (PaO2), peripheral leukocyte counts, total respiratory compliance (TLC) and the increases in peak pressure (Ppeak), Qs/ Qt compared with the baseline values ( P < 0. 05). The increased plasma concentration but reduced activity of AAT was also found in contrast to that in Group NS (P<0. 05). In the BALF, the activity of AAT, TPL, DSPC/TPL were lower than those in Group NS (P<0. 05), but the concentrations of albumin, IL-8, TNFα, the activity of NE and the ratio of W/D were higher than those in Group NS (P <0. 05). The pretreatment of AAT attenuated the deterioration of oxygenation, the reduction of compliance and the deterioration of other physiological and biochemical parameters mentioned above.Conclusion Pretreatment with AAT could attenuate endotoxin-induced lung injury in rabbits. Those beneficial effects of AAT might be due, in part, to reduction in the levels of mediators that could activate neutrophils, in addition to the direct inhibitory effect on neutrophil elastase.
文摘Background： Previous studies conducted in various geographical and ethnical populations have shown that Alpha-1 -antitrypsin （Alpha-1-AT） expression affects the occurrence and progression of chronic obstructive puh-nonary disease （COPD）. We aimed to explore the associations of rs9944155AG, rsl051052AG, and rs1243166AG polymorphisms in the A lpha-1-A T gene with the risk of COPD in Uygur population in the Kashgar region. Methods： From March 2013 to December 2015. a total of 225 Uygur COPD patients and 198 healthy people were recruited as cases and controls, respectively, in Kashgar region. DNA was extracted according to the protocol of the DNA genome kit, and Sequenom MassARRAY single-nucleotide polymorphism technology was used for genotype determination. Serum concentration of Alpha-1-AT was detected by enzyme-linked immunosorbent assay. A logistic regression model was used to estimate the associations of polymorphisms with COPD. Results： The rs1243166-G allele was associated with a higher risk of COPD （odds ratio [OR] = 2.039, 95% confidence interval [CI]： 1.116-3.725, P = 0.019）. In cases, Alpha-1-AT levels were the highest among participants can-yiug rs1243166 AG genotype, followed by AA and GG genotype （χ2 = 11.89, P = 0.003）. Similarly, the rs1051052-G allele was associated with a higher risk of COPD （OR = 19.433, 95% CI： 8.783-43.00, P 〈 0.001）. The highest Alpha-1-ATlevels were observed in cases carrying rs1051052 AA genotype, followed by cases with AG and GG genotypes （χ2= 122.45, P 〈 0.001）. However, individuals with rs9944155-G allele exhibited a lower risk of COPD than those carrying the rs9944155-A allele （OR = 0.121, 95% CI： 0.070-0.209, P 〈 0.001 ）. in both cases and controls, no significant difference in Alpha-l-AT levels was observed among various rs9944115 genotypes. Conclusions： rs 1243166, rs9944155, and rs 1051052 sites of Alpha- I-A Tmay be associated with the COPD morbidity in Uygur population. While rs 1243166-G allele and rs1051052-G allele are associated with an increased risk of developing COPD, rs9944155-G allele is a protect locus in Uygur population. Alpha1-AT levels in Uygur COPD patients were lower than those in healthy people and differed among patients with different rs 1051052 AG and rs 1243166 AG genotypes.
文摘目的探讨苏黄止咳胶囊联合福多司坦片治疗支气管扩张对患者血清肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、α1-抗胰蛋白酶(α1-antitryp sin,α1-AT)、白细胞介素-37(interleukin-37,IL-37)水平的影响。方法选取支气管扩张患者63例,用随机数字表法分为观察组(n=32)和对照组(n=31)。对照组采用福多司坦片治疗,观察组在对照组治疗的基础上联合苏黄止咳胶囊。比较2组患者的治疗疗效、中医证候积分、肺功能指标、TNF-α、α1-AT、IL-37、呼吸状况和不良反应。结果治疗后,观察组的总有效率(96.88%)高于对照组(80.65%),P<0.05;观察组的中医证候积分低于对照组,P<0.05;观察组的第1秒用力呼气容积(forced expiratory volume in one second,FEV1)、用力肺活量(forced vital capacity,FVC)、一氧化碳弥散量占预计值百分比(carbon monoxide diffusion capacity as a percentage of predicted value,DLCO%pred)均高于对照组,P<0.05;观察组的IL-37水平高于对照组,P<0.05,观察组的TNF-α、α1-AT水平低于对照组,P<0.05;观察组的圣乔治呼吸问卷(St.George’s respiratory questionnaire,SGRQ)各维度评分均低于对照组,P<0.05;观察组不良反应发生率低于对照组,P<0.05。结论采用苏黄止咳胶囊联合福多司坦片治疗支气管扩张能有效提高患者的治疗疗效,改善其中医证候,改善TNF-α、α1-AT、IL-37水平、肺功能指标和呼吸功能。
文摘BACKGROUND Alpha-1 antitrypsin deficiency is a rare genetic disease and a leading cause of inherited alterations in plasma protein metabolism(APPM).AIM To understand the prevalence,burden and progression of liver disease in patients with APPM including alpha-1 antitrypsin deficiency.METHODS 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.RESULTS 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%).CONCLUSION Among patients with liver disease,those with APPM experience substantial burden and earlier liver disease progression than patients without APPM.
