Alpha-1-Antitrypsin Pi*MZ variant increases risk of developing hepatic events in nonalcoholic fatty liver disease patients,

AimsHeterozygous alpha-1-antitrypsin (A1AT) Pi*MZ variant has been shown to increase the risk of developing liver cirrhosis in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to determine the association between heterozygous Pi*MZ and Pi*MS variants and development of hepatic decompensation events in NAFLD patients.MethodsWe included patients with NAFLD who also had A1AT genotyping performed from 2005 to 2020. We recorded demographic and clinical variables, and data on hepatic events (ascites, hepatic encephalopathy, esophageal variceal bleed, or hepatocellular carcinoma), if any. We performed binary logistic regression analysis to assess the association between A1AT variants and hepatic events, and calculated Odds ratio (OR) with their 95% confidence intervals (Cl).ResultsWe included 1532 patients with NAFLD, of which 1249 patients had Pi*MM, 121 had Pi*MS, and 162 had Pi*MZ. Of the 1532 patients, hepatic events developed in 521 (34%) patients. The percentage of patients with Pi*MZ variant was significantly higher in patients with hepatic events as compared to patients without hepatic events (18.7 % vs 8.1%, p<0.0001). Pi*MZ variant was noted to significantly increase the odds of developing hepatic events in NAFLD patients, unadjusted OR: 1.82 (1.3–2.5, p<0.001), adjusted OR (for age, sex, body mass index, and diabetes mellitus) 1.76 (1.2–2.5, p = 0.002). Pi*MS variant did not increase the odds of hepatic events in NAFLD patients, OR: 0.92 (0.6–1.4, p = 0.70).ConclusionPatients with NAFLD and A1AT Pi*MZ variant are at increased risk for developing hepatic decompensation. NAFLD patients should be offered A1AT genotyping for risk stratification, counseling, and multidisciplinary intervention for NAFLD.     

Cost-effectiveness analysis of augmentation therapy for severe alpha1-antitrypsin deficiency

A Markov-based decision model was created to assess the cost-effectiveness of augmentation therapy (Aug) for severe alpha1-antitrypsin deficiency, comparing strategies of: (1) no Aug, (2) Aug for life, and (3) Aug until FEV1 is below 35% predicted. A hypothetical cohort of 46-year-old patients with FEV1 49% predicted was followed over time using Monte Carlo simulation across five possible health states: (1) FEV1 50 to 79% predicted, (2) FEV1 35 to 49% predicted, (3) FEV1 below 35% predicted, (4) status-post-lung transplantation, and (5) dead. Treatment for life yielded 7.19 quality-adjusted life-years (QALYs) and cost 895,243 dollars. Treating until FEV1 is below 35% predicted cost 511,930 dollars and produced 6.64 QALYs. "No Aug" cost 92,091 dollars with 4.62 QALYs. The incremental cost-effectiveness ratio was 207,841 dollars/QALY for Aug until FEV1 is below 35% predicted and 312,511 dollars/QALY for the "Aug for life" strategy. In all sensitivity analyses, the incremental cost-effectiveness ratio for Aug for life exceeded 100,000 dollars. The cost of Aug needed to be reduced from 54,765 dollars to 4,900 dollars for the "Aug for life" strategy to be considered cost-effective. We conclude that, compared with other conventionally used health interventions, Aug is relatively less cost-effective. These results should encourage the development of more clinically and cost-effective therapies for alpha1-antitrypsin deficiency.     

Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of alpha1-antitrypsin deficiency in Asia.

The current study focuses on updating estimates of the numbers of individuals carrying the two most common deficiency alleles, protease inhibitor (PI)*S and PI*Z, for alpha1-antitrypsin deficiency (AT-D) in 20 Asian countries. A total of 170 cohorts with 31,177 individuals were selected from 20 Asian countries. The total AT-D populations in the countries selected were: 7,264 ZZ; 36,754 SZ; 6,672,479 MZ; 46,492 SS; and 16,881,108 MS. Marked differences among the Asian countries and regions were also found for the prevalence of the deficiency alleles PI*S and PI*Z. These numbers demonstrate that AT-D is not just a genetic disease that affects smaller numbers than various countries, for example, in Europe. There were marked differences between the prevalence of the PI*S and PI*Z deficiency alleles among these 20 Asian countries as well as among the countries within a given geographic region in Asia. The largest numbers of ZZ phenotypes (3,000-14,000) were in Afghanistan, Pakistan, Saudi Arabia and Thailand; with <1,700 in each of the remaining countries.     

Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries.

The current study focuses on developing estimates of the numbers of individuals carrying the two most common deficiency alleles, PI*S and PI*Z, for alpha1-antitrypsin deficiency (AT-D) in Europe. Criteria for selection of epidemiological studies were: 1) AT phenotyping performed by isoelectrofocusing or antigen-antibody crossed electrophoresis; 2) rejection of "screening studies"; 3) statistical precision factor score of > or = 5 for Southwest, Western and Northern Europe, > or = 4 for Central Europe, > or = 3 for Eastern Europe; and 4) samples representative of the general population. A total of 75,390 individuals were selected from 21 European countries (one each from Austria, Belgium, Latvia, Hungary, Serbia-Montenegro, Sweden and Switzerland; two each from Denmark, Estonia and Lithuania; three each from Portugal and the UK; four each from Finland, The Netherlands, Norway and Spain; five each from Russia and Germany; six from Poland; eight from Italy; and nine from France). The total AT-D populations of a particular phenotype in the countries selected were: 124,594 ZZ; 560,515 SZ; 16,323,226 MZ; 630,401 SS; and 36,716,819 MS. The largest number of ZZ (5,000-15,000) were in Italy, Spain, Germany, France, the UK, Latvia, Sweden and Denmark, followed by Belgium, Portugal, Serbia-Montenegro, Russia, The Netherlands, Norway and Austria (1,000-2,000), with < 1,000 in each of the remaining countries. A remarkable lack in number of reliable epidemiological studies and marked differences among these European countries and regions within a given country was also found.     

The effect of augmentation therapy on bronchial inflammation in alpha1-antitrypsin deficiency

alpha1-Antitrypsin (AAT) deficiency predisposes to bronchitis and emphysema associated with neutrophilic airway inflammation. The efficacy of augmentation therapy has not been proven clinically or by demonstrating an effect on airway inflammation. We treated 12 patients with four infusions of Prolastin (60 mg/kg) at weekly intervals and monitored both the serum and secretion concentrations of AAT as well as markers of neutrophilic inflammation, including myeloperoxidase, elastase, and the neutrophil chemoattractants interleukin-8 and leukotriene B(4). Serum AAT rose and was maintained above the protective threshold. In addition, AAT concentrations in the sputum rose from a mean of 0.17 microM (SEM +/- 0.04) before therapy to concentrations similar to nondeficient subjects (0.43 +/- 0.12) 1 week after the first infusion (p < 0.01). This was associated with a reduction in elastase activity (p < 0.002) and the chemoattractant leukotriene B(4) (p < 0.02), which fell from a median baseline value of 13.46 nM (range, 4.17-55.00) to 8.62 nM (4.23-21.59) the day following the last infusion. Although median values for myeloperoxidase and interleukin-8 also fell, the changes failed to achieve statistical significance. In summary, short-term therapy with AAT increased lung secretion concentrations and was associated with a fall in leukotriene B(4), which is thought to be central to the airway inflammation of AAT deficiency.     

血清降钙素原指导 AECOPD 抗菌治疗的思考

减少抗菌药物的暴露是减少细菌耐药的重要措施,已有部分临床试验支持降钙素原(PCT)指导慢性阻塞性肺疾病急性加重(AECOPD)抗菌治疗能安全减少其暴露。由于研究的局限性及缺乏微生物学数据的支持,PCT 指导 AECOPD 抗菌治疗的价值仍没有可靠的结论。然而,聚合酶链反应因其鉴定病原体的高敏感性和特异性有望建立起 PCT 与不同病原体感染之间的明确关系,从而更进一步评价 PCT 指导抗菌治疗的作用。     

Pulmonary function in heterozygotes for alpha,-antitrypsin deficiency: a case-control study.

In this paper we present the initial cross-sectional data from a prospective study of lung aging in heterozygotes for alpha 1-antitrypsin deficiency. Using a case-control design, our cases included 37 heterozygotes for alpha 1-antitrypsin deficiency, protease inhibitor phenotypes MZ and MS, selected because they were parents of children with homozygous alpha 1-antitrypsin deficiency identified in a statewide newborn screening program between 1971 and 1974. All of the heterozygotes were less than 40 yr of age. Our control subjects were selected from a random sample of a working population participating in a longitudinal study of lung aging, using a 2:1 match of control subjects to cases, matching age, sex, ethnic origin, and smoking. Using a respiratory symptom questionnaire, spirometry, and the single-breath N2 test, we found no significant difference between heterozygotes and control subjects in terms of respiratory symptoms or pulmonary function data. We conclude that to 40 yr of age, the heterozygous phenotype (Pi MZ and MS) is not a risk factor for impairment of pulmonary function.     

Detection of carotenoids in blood donors taking Orobronze: a cautionary note

During the summer, plasma samples from eight blood donors at this transfusion centre were found to have a bright orange colour. All donors appeared to be healthy and haematological tests showed no abnormality. Extracts of lipid from the plasma revealed the presence of the carotenoid canthaxanthin and other carotenoid metabolites which were identified by thin-layer chromatography and high-pressure liquid chromatography, light absorbtion and mass spectrometry. On questioning the donors it was found that they had been taking a course of 'Orobronze' (an oral 'bronzing' treatment containing canthaxanthin). Canthaxanthin was still detectable in the plasma several months after the donors had ceased taking the capsules. At present it seems that there would be no deleterious effects on healthy individuals taking orobronze. The full implications of the presence of canthaxanthin in plasma transfused to patients do, however, require further investigation of carotenoid metabolism in man.