Multi-society expert panel consensus guidance regarding clinical assessment and clinical trial endpoints in adults with alpha-1 antitrypsin deficiency-associated liver disease
Multi-society expert panel consensus guidance regarding clinical assessment and clinical trial endpoints in adults with alpha-1 antitrypsin deficiency-associated liver disease
Background & aims: Alpha-1 antitrypsin deficiency-associated liver disease (AATD-LD) remains underrecognized despite its significant contribution to morbidity and mortality in adults with the PiZZ genotype. Lack of standardized definitions, diagnostic criteria, and staging impedes timely diagnosis and therapeutic development. To address these gaps, a multi-disciplinary expert panel convened under the auspices of the American Gastroenterological Association in collaboration with the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and Alpha-1 Foundation to develop consensus recommendations for nomenclature, diagnosis, staging, and clinical trial endpoints in AATD-LD.
Methods: An international multi-disciplinary expert consensus synthesized data from recent epidemiologic, histopathologic, and noninvasive biomarker studies related to AATD-LD. Expert opinion was integrated with published evidence to establish case definitions, staging algorithms, and clinical trial endpoint criteria.
Results: AATD-LD is defined by the presence of liver enzyme (ie, aspartate aminotransferase, alanine aminotransferase, or γ-glutamyl transferase) elevations-which may be episodic-and/or liver fibrosis (≥F2) in adults with AATD, particularly those with the PiZZ genotype. Liver stiffness measurement by means of noninvasive elastography (eg, vibration-controlled transient elastography and magnetic resonance elastography) was identified as the preferred method for staging fibrosis, with liver stiffness measurement ≥8 kPa by means of vibration-controlled transient elastography as a threshold for clinically significant fibrosis. Aspartate aminotransferase-to-platelet ratio (<0.5) and fibrosis-4 index (<1.3) (low risk for advanced liver disease) were endorsed for risk stratification, although their sensitivity is limited. A foundational, tiered algorithm was developed to guide longitudinal monitoring and staging, incorporating serial noninvasive testing and timely referral for liver transplantation evaluation. For clinical trial design, adults with F2-F4 fibrosis were recommended for inclusion in phase 3 trials; earlier stages (eg, F1) may be appropriate for phase 1-2 safety studies and patients with cirrhosis may be excluded, depending on therapeutic class. Preservation of pulmonary function was not deemed necessary for inclusion in trials of therapies that increase AAT levels via DNA or RNA editing. The consensus primary efficacy endpoint is a ≥1-stage improvement in fibrosis.
Conclusions: These consensus statements provide a unified framework for diagnosing, staging, and studying AATD-LD. Broad adoption will improve disease recognition, optimize clinical management, and facilitate therapeutic development.
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