Clinical Utility of VCTE for Liver Fibrosis in People Living with Alpha-1 Antitrypsin Deficiency

Boeckmans, et al. Clinical Utility of Non-Invasive Tests for Liver Fibrosis in People Living With Alpha-1 Antitrypsin Deficiency.

Severe alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition caused by mutations in the SERPINA1 gene, characterized by low systemic levels of alpha-1 antitrypsin due to its retention in the liver. Consequently, it predisposes individuals to the development of chronic obstructive pulmonary disease and liver cirrhosis.

It is estimated that approximately 20%–35% of adults living with AATD due to the Pi*ZZ genotype will develop liver fibrosis, and approximately 15% of adults who present with AATD-related liver disease require a liver transplantation.

The objective of this study was to review clinical evidence on clinical utility and to establish consensus guidelines for non-invasive tests, in assessing liver fibrosis in people living with alpha-1 antitrypsin deficiency.

A prospective study of 737 Pi*ZZ individuals with median follow-up of 3.5 years demonstrated that baseline liver stiffness measurement (LSM) using VCTE effectively predicted incident major adverse liver outcomes (MALOs).

Participants who developed liver endpoints exhibited elevated baseline LSM values (23.6 kPa, consistent with cirrhosis) compared to those with endpoint-free survival (5.3 kPa).

LSM by VCTE showed excellent prognostic utility for incident MALOs with an area under the receiver operating characteristic curve (AUROC) of 0.98 at 3 years and 0.95 at 5 years.

LSM < 7.1 kPa ruled out advanced fibrosis excluding individuals who did not develop MALOs at ≥ 2 years’ follow-up.

Type 2 diabetes mellitus was associated with an 8-fold increased risk of having VCTE-LSM ≥ 7.1 kPa, representing a “double-hit” mechanism in patients with MASLD .

Recent Delphi consensus recommendations propose systematic LSM by VCTE measurement in severe AATD patients:

• LSM < 8 kPa (re-evaluation in 2-3 years)
• LSM ≥8-13 kPa (further testing with MRE and/or ELF, or liver biopsy if discordant results from ≥2 NITs, otherwise re-evaluation in 1-2 years)
• and LSM ≥13 kPa or clinical signs of advanced liver disease requiring immediate specialist evaluation (See Figure 1)

PiMZ and PiSZ carriers have 2 to 3x higher fibrosis/cirrhosis risk; annual liver function testing and VCTE every 5 years are recommended, following PiZZ algorithms.

Figure 1: Potential strategy for liver disease follow-up

LSM by VCTE is the most effective predictor of significant fibrosis and adverse liver outcomes in AATD patients, with excellent prognostic accuracy (AUROC 0.98 at 3 years, 0.95 at 5 years).

LSM thresholds enable effective risk stratification: LSM < 7.1 kPa rules out advanced fibrosis, while elevated baseline LSM (23.6 kPa vs 5.3 kPa) predicts future liver complications.

Optimal AATD liver monitoring could be done using a combination of LSM by VCTE with blood-based biomarkers, using consensus-based LSM cutoffs (< 8 kPa, 8-13 kPa, ≥13 kPa) to guide surveillance frequency and additional testing requirements.

“Since LSM through VCTE is a point-of- care test and increasingly available, regular screening employing LSM with a cutoff of 8 kPa could be a convenient and accurate strategy for finding individuals at risk for liver disease progression, and potentially also select patients that could benefit from liver-directed treatment”

APRI : AST to platelet ratio; FIB-4: fibrosis-4 Score; LSM, liver stiffness measurement; VCTE, vibration-controlled-transient-elastography