| Title: | Original research: Amplification of genetic and metabolic factors in alpha-1 antitrypsin deficiency. |
| Journal: | Hepatology |
| Published: | 11 Mar 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41812027/ |
| DOI: | https://doi.org/10.1097/hep.0000000000001710 |
Publication 17414
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Abstract
BACKGROUND AND AIMS: Severe (Pi*ZZ) and heterozygous (Pi*MZ) alpha-1 antitrypsin deficiency (AATD) confer increased liver- and lung-related mortality, but the phenotype is highly variable. We aimed to evaluate the impact of obesity and diabetes mellitus on individuals with/without AATD.</p>
APPROACH AND RESULTS: Cohort 1 prospectively recruited 1678 Pi*ZZ adults from an international initiative with a systematic liver assessment. 983 participants had a longitudinal follow-up. The data were compared to 16,768 Pi*MZ and 415,208 non-AATD individuals from the United Kingdom Biobank (cohort 2). Findings were ascertained by multivariable adjustment and propensity score matching. At baseline, diabetes was present in 52 (3%), overweight (BMI 25.0-29.9 kg/m2) in 540 (52%) and obesity (BMI≥30 kg/m2) in 266 (32%) Pi*ZZ adults. Pi*ZZ individuals with diabetes showed higher transaminases and surrogates of advanced liver fibrosis (APRI≥1.0, LSM≥15 kPa) were four to six times more common (adjusted Odds Ratio (aOR) 5.7/4.3, p<0.01). Elevated transaminases were rare among lean Pi*ZZ subjects, but more common in overweight (aOR 1.5/2.0) and obese Pi*ZZ participants (aOR 2.1/2.9). APRI≥1.0 was more than four times elevated in obese vs. lean Pi*ZZ individuals (aOR 4.1, p<0.001). During a median follow-up of 4.2 years, 54 Pi*ZZ participants experienced a hepatic and 64 a pulmonary endpoint. While Pi*ZZ participants with diabetes/obesity had an increased risk of hepatic endpoints (aHR 6.03/3.38, p<0.001) compared with non-diabetic/lean Pi*ZZ subjects, overweight was associated with a decreased risk of pulmonary endpoints (aHR 0.45, p=0.004).</p>
CONCLUSIONS: Our data demonstrate the interaction between genetic and metabolic risk factors in AATD and provide evidence for patient management.</p>
35 Authors
- Christina Schrader
- Malin Fromme
- Paul Ellis
- Audrey Payancé
- Mattias Mandorfer
- Jan Stolk
- Bart van Hoek
- Katrine H Thorhauge
- Monica Pons
- Marc Miravitlles
- Guido Stirnimann
- Sona Frankova
- Jan Sperl
- Andreas E Kremer
- Katharina Remih
- Emily K Weber
- Lorenz Balcar
- Annelot D Sark
- Benedikt Schaefer
- Joanna Chorostowska-Wynimko
- Elmar Aigner
- Sophie Gensluckner
- Heike Bantel
- Jef Verbeek
- Zoe Mariño
- Rohit Loomba
- Heinz Zoller
- Michael Trauner
- Joan Genesca
- Virginia Clark
- Aleksander Krag
- Noel G McElvaney
- William J Griffiths
- Alice M Turner
- Pavel Strnad
1 Application
| Application ID | Title |
|---|---|
| 148742 | Multiomic signature of digestive disorders |
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