Liver involvement in alpha1-antitrypsin deficiency (AAT deficiency)

AAT deficiency is a commonly overlooked hereditary disorder. It constitutes the third most prevalent lethal hereditary disease worldwide. Individuals of all ages and all ethnic groups are affected. The highest incidence of the disease is found in our part of the world (Western and Northern Europe).

Severe and milder forms of AAT deficiency are due to the inheritance of different genotypes (e.g. genetically defined hereditary variants) of the AAT gene. Nearly 10% of the European population carry at least one abnormal variant of the AAT gene. Currently, there are over 150 known AAT genotypes, but it remains unclear whether and to what extent they affect the liver. For the classic severe forms of the disease (so-called ‘PiZZ’ or ‘PiSZ’ genotype) the number of affected individuals is estimated to exceed 60,000 in our region alone. These individuals can develop a range of liver disorders including liver cirrhosis and liver cancer. The milder forms of AAT-deficiency (such as the PiMZ genotype) are estimated to affect up to 10 million people in Europe alone.  Liver disease can develop even in the milder genotypes, particularly when other problems such as viral hepatitis, alcohol or metabolic stress put an additional strain on the liver. Liver cirrhosis is the end-stage of liver damage characterized by extensive scarring and carries a poor prognosis. Liver cirrhosis can result in various complications, e.g. a greatly elevated risk of liver cancer or severe bleeding. With declining liver function, it may lead to a multi-organ failure and in this case liver transplantation is the only option. To avoid these severe complications, an early diagnosis and appropriate management is of crucial importance. For example, potentially treatable liver diseases (e.g. viral hepatitis, autoimmune disorders or metabolic syndrome) need to be identified and cared for to reduce the progression of liver injury.

Besides hurting the lungs, AAT deficiency can lead to considerable liver damage. Up to 50% of adult patients with AAT deficiency develop liver injury. Therefore, liver involvement is the second most common cause of diminished quality of life and lower life expectancy in patients with AAT deficiency. Despite this fact, chronic liver damage in patients with established AAT deficiency is often not diagnosed until a very late stage. There are various reasons for this: Affected patients with chronic liver damage generally have no symptoms or only unspecific complaints. Typical symptoms emerge only at later stages of liver cirrhosis. Furthermore, routine diagnostic measures such as liver function tests in the blood often reveal no abnormalities. In addition to that, neither physicians nor patients are sufficiently aware of the risks of AAT deficiency-associated liver disease and because of that a liver specialist rarely gets involved. Given this situation, chronic liver damage is often diagnosed at a very late stage. In case of a delayed diagnosis, the complications of liver damage can no longer be effectively prevented. Finally, due to insufficient research data, there is currently no established preventive care plan for liver involvement in AAT deficiency, although such guidelines are available for lung involvement. To improve this situation, we are validating techniques for diagnosing and quantifying liver involvement in patients with AAT deficiency. Another goal of our study group is to define parameters useful for monitoring the course of the disease and to define a plan for preventive care.

In summary, early assessment of a liver involvement together with appropriate monitoring of the disease course is of critical importance, as AAT deficiency is a hereditary disease that is as yet incurable. It is our mission to detect liver damage in patients with AAT deficiency at an early stage and where possible to provide a treatment. Through long-term monitoring plans, we hope to improve the care of affected patients while our research aims to developing better diagnostic and therapeutic procedures.

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