Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation.

BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.

Using web-based videos to improve inhalation technique in COPD patients requiring hospitalization: A randomized controlled trial.

BACKGROUND: Inhalation errors frequently occur in patients receiving inhalation treatment, which can significantly impair treatment success. While this underscores the importance of inhalation training, the role of modern web-based instructional videos has not yet been investigated. METHODS: A randomized controlled trial using standardized checklists (10 items: preparation, N = 3, inhalation routine, N = 6, and closure of inhalation, N = 1) was carried out to determine the relative effects of web-based, device-specific videos versus standard personal instruction on reducing multiple (≥2) inhalation errors in severe COPD patients requiring hospitalisation. Investigators assessing inhalation errors were blinded to the intervention. RESULTS: Multiple handling errors were recorded at baseline in 152 out of 159 patients (95.6%). Each teaching method led to a similar reduction in errors (videos: from 4.2±1.6 to 1.5±1.5 errors; personal instruction: from 3.8±1.5 to 1.3±1.6; p<0.0001), although non-inferiority of web-based video teaching could not be confirmed statistically due to an unpredictably high number of patients in both groups still making multiple handling errors (44.0% versus 40.3%, mean difference 3.7%; 95%CI [-12.0-19.4%]). CONCLUSION: Multiple inhalation errors regularly occur in severe COPD patients requiring hospitalisation. Web-based video teaching is capable of reducing inhalation errors. However, compared to personal instruction non-inferiority could not be established. This was due to an unexpectedly high number of patients with persisting inhalation errors despite training. TRIAL REGISTRATION: Clinical trial Registration: German Clinical Trial Register, DRKS 00004320.

Optimizing inhalation technique using web-based videos in obstructive lung diseases.

BACKGROUND: Inhaled agents are widely used in the treatment of chronic airway diseases. Correct technique is required to ensure appropriate drug deposition, but poor technique is common. This study investigated whether inhalation technique could be improved by patient training using short videos from the German Airway League. METHODS: Outpatients from a university hospital respiratory clinic who had incorrect inhalation technique were asked to demonstrate this again immediately after viewing the training videos, and after 4-8 weeks' follow-up. Inhalation technique was rated by a study nurse using specific checklists. RESULTS: One hundred and twelve patients with obstructive lung disease treated with inhaled bronchodilators or corticosteroids were included. More than half (51.8%) had at least one mistake in inhalation technique at baseline. Of these, most (88%) understood the training videos, 76% demonstrated correct device use immediately after training, and 72% were still able to demonstrate correct inhalation technique at follow-up (p = 0.0008 for trend). In addition, the number of mistakes decreased significantly after video training (by 1.82 [95% confidence interval 1.39-2.25]; p < 0.0001 vs. baseline). CONCLUSIONS: German Airway League inhalation technique training videos were easy to understand and effectively improved inhalation technique in patients with airway diseases.