News from the Alpha1 team at the RWTH Aachen University Hospital

Barbara Burbaum, Malin Fromme, Karim Hamesch and Pavel Strnad

The Alpha-1 team at the University Hospital RWTH Aachen, led by Prof. Strnad, has been investigating liver involvement since 2015. Since then, our understanding of the consequences for the liver in alpha-1 antitrypsin deficiency has expanded significantly. The Aachen team is now the European reference center for liver involvement in alpha-1 antitrypsin deficiency and is supported by the European Commission (European Reference Networks) and the European Association for the Study of Liver Diseases (EASL registry grant).

Approximately ten percent of Europeans carry a mutation in the alpha-1 antitrypsin gene (the so-called SERPINA1 gene). The classic Pi*Z mutation is present in two to four percent of all Europeans. It has now become known that the presence of this mutation on even a single gene copy (heterozygous form, Pi*MZ genotype) increases the risk of liver disease, especially when combined with other factors such as excessive alcohol consumption, obesity, or diabetes. This has been demonstrated in recent publications by the Aachen team. Through Europe-wide collaboration with other scientists, pulmonologists, and, above all, patient support groups, the team succeeded in establishing the largest cohort of Alpha-1 patients and conducting a systematic characterization of their liver function. Currently, approximately 1,500 participants from over eleven European countries have been examined. For their latest publication, the Alpha1 team supplemented the data with a population-based cohort from the UK comprising approximately 450,000 patients.

The Pi*MZ genotype is associated with slightly elevated liver enzyme levels on average, although these remain within the normal range in most subjects. Liver tissue samples have shown that Pi*MZ subjects frequently already exhibit alpha-1 inclusion bodies, although these were less common than in individuals with the homozygous Pi*Z mutation (Pi*ZZ genotype). These inclusion bodies were particularly frequent in subjects with advanced liver disease. However, the absence of inclusion bodies could not definitively rule out the presence of alpha-1 antitrypsin deficiency in either the Pi*MZ or Pi*ZZ genotype, highlighting the importance of genotyping for diagnosing the disease.

Furthermore, Pi*MZ subjects had increased liver stiffness compared to those without the mutation, but lower stiffness than subjects with severe alpha-1 antitrypsin deficiency (Pi*ZZ). Liver stiffness provides reliable information about the degree of liver scarring. In summary, the degree of liver disease in heterozygous Pi*MZ patients lies between that of non-carriers and Pi*ZZ patients. Liver disease is primarily promoted by metabolic factors such as obesity and diabetes, as well as excessive alcohol consumption.
Previous studies by the Aachen Alpha1 group have already shown that individuals with Pi*ZZ have up to a twenty-fold increased risk of developing liver cirrhosis. Professor Strnad remains optimistic: "Through our research in the field of alpha-1 antitrypsin deficiency, we now have the opportunity to detect the development of liver fibrosis at an early stage, and, thanks to the current drug trials, for the first time, we also have the chance to help those affected." The Aachen team is currently participating in a phase II trial in which Pi*ZZ patients with advanced liver fibrosis receive an injection of a so-called siRNA. This medication prevents the production of alpha-1 antitrypsin, thus relieving the liver of further stress. Furthermore, another study will begin soon. In this study, the alpha-1 antitrypsin will be removed from the liver so that it can exert its remaining residual activity in the lungs.

Due to current events: Alpha-1 antitrypsin deficiency and COVID-19?

The current situation, triggered by the coronavirus, also raises many questions for patients with alpha-1 antitrypsin deficiency. SARS-CoV-2 is an RNA virus primarily characterized by pneumonia. The effects of this novel virus are currently under investigation, as numerous consequences have been observed in other organs as well. While no reliable statements can yet be made about the interaction between SARS-CoV-2 and alpha-1 antitrypsin deficiency, it is generally assumed that the extent of the risk is (partly) determined by the degree of existing organ damage. In this regard, a large study from Great Britain, which analyzed a total of 5,683 cases of deceased, hospitalized COVID-19 patients, is worth mentioning. Age was one of the greatest risk factors. Those over 80 years of age had a 12-fold increased risk compared to the 50- to 59-year-old age group. Furthermore, male sex is associated with twice the mortality rate. Transplant recipients experience a four- to fivefold increased mortality rate compared to hospitalized COVID-19 patients. Generally, patients with pre-existing liver disease show a 1.8-fold increased mortality rate. It is currently recommended that ongoing therapy for chronic conditions, even those with immunosuppressive effects, should not be interrupted. The same applies to alpha-1 augmentation therapy.