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Amplification of genetic and metabolic factors in alpha-1 antitrypsin deficiency
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DOI：10.1097/HEP.0000000000001710.png)
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Abstract
En 中文
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. Approach and Results: Cohort 1 prospectively recruited 1678 Pi*ZZ adults from an international initiative with a systematic liver assessment. In all, 983 participants had a longitudinal follow-up. The data were compared with 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/m(2)) in 540 (52%), and obesity (BMI >= 30 kg/m(2)) 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 4-6 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 4 times elevated in obese versus 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). Conclusions: Our data demonstrate the interaction between genetic and metabolic risk factors in AATD and provide evidence for patient management.
Keywords:
BMI
diabetes
liver fibrosis
lung emphysema
SERPINA1
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