Care gaps are present across the care pathway for A1ATD-related liver disease; it is significantly underdiagnosed, suffers from a lack of awareness, and currently there are no approved pharmacological treatments. Can case-finding play a role in improving this picture?
What is A1ATD?
It’s a genetic condition, characterised by low plasma levels of a protein called alpha-1 antitrypsin (AAT) (less than 0.9 g/L). It is a result of point mutations in the SERPINA1 gene (1) which is responsible for producing AAT. AAT is made in the liver and regulates the activity of neutrophil elastase to protect the alveoli within the lungs. Deficiency of AAT can predispose people to liver and lung disease (2), although via different mechanisms.
How does it impact the liver?
➡️ Liver disease is most likely to develop in people who carry the PiZ allele, due to misfolding of the AAT protein causing it to build up in the liver. This leads to progressive liver cell injury, resulting in fibrosis and cirrhosis.
➡️ The risk is highest in those with two PiZ alleles (homozygous), but can also occur in those with one copy (heterozygous), especially if other environmental or genetic risk factors are present.
➡️ The PiZZ (homozygous) mutation is responsible for over 95% of severe cases of A1ATD (1).
➡️ In the UK, around 17,000 people have the PiZZ genotype (3).
➡️ Individuals with the PiZZ genotype are 20 times more likely to develop liver fibrosis, cirrhosis, and hepatocellular carcinoma compared to those without the mutation (4).
Where are the care gaps?
Diagnosis
➡️ There is a lack of awareness of A1ATD amongst non-specialist physicians (5).
➡️ The symptoms overlap with other common conditions such as COPD and asthma (6).
➡️ There is no population-wide screening programme (6).
➡️ It has variable genetic expressivity due to both the way it is inherited and epigenetic risk factors.
➡️ Currently, there are no well-established guidelines on best practice.
Treatment
➡️ Liver transplantation is the only curative option and is only considered when liver failure develops (1).
➡️ Currently, there are no licensed pharmacological treatments for A1ATD-related liver disease.
➡️ However, several promising therapies are currently undergoing clinical trials.
Why is case-finding useful for A1ATD?
By using blood test results going back over many years, clinicians may find trends that indicate progressing liver and lung disease, offering significant clinical and public health benefits.
Improving early diagnosis:
➡️ Earlier diagnosis allows for more timely intervention for symptom management, augmentation therapy, pulmonary disease monitoring, HCC surveillance, and targeted lifestyle intervention.
➡️ This then allows for cascade testing to identify family members who may be at risk of A1ATD, allowing for earlier diagnosis, disease monitoring, and improved prognosis.
➡️ Cascade testing can identify asymptomatic carriers, allowing for genetic counselling to support patients with family planning decisions (7).
Improving research into new therapies:
Case-finding can play a role in improving clinical trials for A1ATD by streamlining the recruitment process and increasing the number of eligible participants who meet the inclusion criteria.
➡️ It enhances diversity and health equity by expanding recruitment across primary and secondary care, as well as underserved populations (8).
➡️ Targeted genotyping and stratification of high-risk individuals reduce the time and costs associated with traditional recruitment efforts.
➡️ Identifying asymptomatic or treatment-naïve cohorts allows a larger group of eligible participants to be identified at earlier stages of the disease process, facilitating recruitment into disease-modifying therapeutic trials.
Case-finding can also raise awareness amongst clinicians and people with the disease, supporting education and interest in research participation.
How can you implement case-finding for A1ATD and other chronic liver diseases? Get in touch: predictivehealthintelligence.co.uk
References:
2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)66781-5/abstract.
3. https://publications.ersnet.org/content/erj/56/6/2001441
5. https://www.ccjm.org/content/ccjom/61/6/461.full.pdf
7. https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01352-5
8. https://www.tandfonline.com/doi/full/10.3109/15412555.2013.763782