Author
Summary: Prof. Gratiana Steinkamp, as published in Alpha1 Journal 1/2023.
The fundamental disorder in AAT deficiency is that the altered AAT proteins clump together, form aggregates, and accumulate in cells. Such protein aggregation is a widespread problem that also affects other major diseases. Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) belong to this group. This is one reason why the pharmaceutical industry is increasingly interested in the topic. AAT deficiency can be considered a model disease in this context.
The Alpha1 Consortium was founded in 2015. Thanks to close collaboration between patient advocacy organizations and researchers, important new insights have been gained. We now have a much more precise understanding of which mutations affect the liver, particularly in PiMZ and PiZZ. More than 1,800 participants have been examined, some multiple times, and members of the research group have authored internationally recognized publications as well as more than ten medical dissertations and two postdoctoral theses on AATM and liver involvement.
Evaluation of liver health
Acute liver damage is assessed using standard blood tests to check liver function. These tests can also be performed by a general practitioner. Values such as AST and ALT indicate the liver's condition over the past few days. Any acute increases usually subside quickly. Individuals with PiZZ (a specific liver enzyme) have elevated AST/ALT levels in up to 151 of their blood tests. Anyone with PiZZ who repeatedly experiences elevated liver enzyme levels should be alert and undergo further investigation.
A key aspect of AATM is the assessment of chronic liver damage. The most accurate and reliable method is a liver biopsy, which involves taking a tissue sample. However, this procedure is painful and cannot be considered a routine examination. A specialized ultrasound examination of the liver is the FibroScan. As the name suggests, it can detect fibrosis, the remodeling of the liver tissue. The "stiffness" of the liver is measured in kPa, with values below 7.1 kPa considered largely harmless. These measurements are categorized into fibrosis stages 0 (normal) to 4 (liver cirrhosis). Stiffness values of ≥7.1 kPa indicate at least moderate fibrosis (stage 2).
When researchers compared the results of liver biopsies with FibroScan data, they were able to easily detect advanced stages 3 and 4 with the FibroScan device, but not stages 1 and 2. Of the individuals examined using PiZZ, 71 TP3T had severe stage 3 and 51 TP3T had stage 4, consistent with liver cirrhosis. 781 TP3T patients showed normal FibroScan results, meaning that only 221 TP3T showed signs of at least moderate fibrosis.
Compared to controls, individuals with PiMZ have only a slightly increased risk of developing liver cirrhosis. In contrast, this risk is approximately 20 times higher in patients with PiZZ. Furthermore, a small proportion of PiZZ patients with liver disease will eventually develop liver cancer.
A simple way to roughly assess liver health is the APRI score, which anyone can calculate themselves. You need the liver enzyme AST (AST) in IU/L, the corresponding upper limit of normal from the laboratory, and the platelet count (thrombocytes) in 10⁶/L. First, divide the AST value by its normal value, then divide this number by the platelet count, and finally multiply by 100. Online calculators can also be used. If the liver shows advanced liver fibrosis in a FibroScan measurement, the corresponding APRI values are usually above 1.0. Values below 0.5 are more indicative of scarred liver, but do not rule it out.
„"The assessment of chronic liver damage is particularly important in the AATM."“
Liver involvement in the long-term course
A large study in Aachen followed over 500 PiZZ patients for at least one year, including a comprehensive examination program at the beginning and at least one extensive interview during the follow-up period. Over an average follow-up of 3.6 years, 26 of these patients died, 12 of them due to their liver disease. Lung and liver transplants were required in 19 and 5 participants, respectively. In addition, four patients developed severe decompensated liver cirrhosis.
The researchers evaluated the results of the FibroScan scans at baseline and compared them to later findings of serious liver problems. Patients who subsequently developed serious liver problems almost always had a liver stiffness above 10 kPa at baseline, while the measurements of the other study participants were mostly below 7.1 kPa. This showed that the FibroScan can indeed provide predictions regarding liver involvement.
Approximately one in 30 Germans carries the PiMZ genotype, and those affected are generally not ill. However, they should be aware of risk factors for their liver, as they develop liver fibrosis somewhat more frequently than the general population. The combination of PiMZ with obesity (i.e., a body mass index (BMI) over 30 kg/m²) and/or diabetes is particularly unfavorable. The risk of alcohol-related liver cirrhosis is also more than five times higher in PiMZ individuals. Data from over 17,000 PiMZ individuals were analyzed from a biobank project in the United Kingdom regarding their alcohol consumption. Increased liver abnormalities were only observed when consumption exceeded 60 g of alcohol per day for men and 40 g per day for women. Consumption below these amounts resulted in similar findings for PiMZ individuals as in the control group; however, some people may be more sensitive to alcohol. Therefore, if liver values are elevated, it makes sense to stop consuming alcohol, at least in the medium term, to see if this leads to improvement.
The overall recommendation for people with PiMZ is that they should consult a specialist as soon as liver changes are detected. The goal is to identify the underlying causes and prevent the progression of the dysfunction.
New therapeutic approaches for the liver
Due to the mutation in the SERPINA1 gene, a defective Z-AAT is produced in AATD. It is misfolded and therefore has an altered spatial structure. Consequently, it accumulates in liver cells, similar to waste products. This Z-AAT deposition acts like a toxin for the liver and damages the tissue over time.
This year, too, the team around Pavel Strnad offered the opportunity to have a Fibroscan including a blood test during the information day.
New treatment approaches aim to prevent the production of the misfolded Z-AAT. This occurs not at the gene or DNA level itself, but at the underlying RNA level. One promising substance is fazirsiran, a novel siRNA (small interfering RNA) therapeutic. Fazirsiran is intended to reduce the production of the mutated AAT and thus halt the progression of liver disease. A small study with sixteen patients tested fazirsiran at a dose of 100 or 200 mg, administered subcutaneously every twelve weeks. Just two weeks after the start of treatment, doctors were able to detect less Z-AAT in the blood than before. This reduction persisted for over a year with repeated administration of fazirsiran. Z-AAT was also measured in liver tissue samples from the study participants. In the follow-up examination, 83% less Z-AAT was found than before the start of therapy. The liver enzymes ALT and gamma-GT also decreased significantly over the course of the study and mostly fell within the normal range. Lung function remained unchanged on average during the twelve-month study period. The researchers did not observe any side effects that led to discontinuation of the study medication.
Belcesiran is a similar siRNA drug from another manufacturer. A Phase 2 trial is currently underway, which can also include individuals with liver cirrhosis. Both siRNA drugs will undergo further thorough testing in the coming years.
Furthermore, studies are investigating substances with entirely different mechanisms of action. The CRISPR method, also known as gene editing, offers gene therapy for AATD. Substances that can correct the misfolding of Z-AAT, and which have been used successfully for years in a similar form to treat the hereditary disease cystic fibrosis, are intended to correct this misfolding. Researchers also have ideas for new medications at the RNA level. These diverse efforts to correct the underlying defect give great hope to people with AATD.
In closing, the speaker highlighted the ongoing Aachen liver study. During the Alpha1 information day, the team is offering participants the opportunity to undergo thorough and free examinations by specialists. At the same time, participants are supporting research into liver disease in AATD.
