Alpha-1 antitrypsin deficiency – What happens in the liver?

Dr. Pavel Strnad, European Reference Centre for Alpha-1 Antitrypsin Deficiency, University Hospital RWTH Aachen

At the beginning of his presentation, the speaker summarized the most important basics regarding liver involvement in AATD (see Journals 1/2017 and 1/2018). He then presented the latest analyses of the Alpha-1 Liver Study.

The Alpha-1 Liver Study

Many conference attendees have already participated in the study as volunteers. The project is taking place in nine European countries and is aimed at all patients with AATD and their relatives. Patients with severe AATD (PiZZ/PiSZ) are strongly encouraged to participate due to their increased risk. The researchers aim to systematically record and comprehensively describe the extent of the liver disease.
Patients are asked about their symptoms using questionnaires, blood samples are analyzed, and liver stiffness is measured using a FibroScan® device. Measurements above 7.1 kPa (kilopascals) indicate fibrosis (fibrosis) of the liver.
For the participating patients, the study offers the advantage of providing comprehensive information about their liver health. If the findings indicate liver disease, the doctors recommend a liver biopsy, depending on the individual circumstances. This involves the direct removal of a tiny piece of liver tissue. Under a microscope, the liver cells can be closely observed, and the liver disease can be classified.

Results from patients with PiZZ type

To date, approximately 600 patients with AATM of the PiZZ type have been examined. Among their relatives, about 250 people with the PiMZ type and 234 individuals with completely healthy genetics (PiMM) participated.
The liver enzymes ALT and AST (formerly known as GPT and GOT) are the typical liver enzymes that general practitioners always order first. Together with the bile enzymes bilirubin, gamma-GT, and alkaline phosphatase (ALP), they provide a snapshot of liver function. Only later in the course of the disease do markers of liver production become abnormal, including prothrombin time (PT/INR), albumin, and pseudocholinesterase.
As expected, the Alpha-1 Liver Study showed that most people with PiZZ type had normal levels of ALT, AST, GGT, and alkaline phosphatase. Abnormal values were found in only 15-201 TP3T patients. In FibroScan®, liver stiffness was normal or only slightly elevated in 611 TP3T of all PiZZ patients. Liver fibrosis was suspected in 231 TP3T patients, 111 TP3T had severe liver fibrosis, and 51 TP3T had liver cirrhosis.
Besides FibroScan, there are alternative methods that can provide indications of existing liver disease. For example, the liver enzyme AST and the platelet count (thrombocytes) can be used. From these two values, the APRI value (AST/platelet ratio index) can be calculated separately for men and women. Normally, it is below 0.5. A value above 0.5 indicates incipient liver fibrosis, and a value above 1.0 indicates advanced liver fibrosis. In PiZZ patients, the APRI value was ten times more likely to be above 1.0 than in subjects without AATD. When liver fibrosis was assessed using FibroScan (where a value above 10 kPa indicates advanced liver fibrosis), the risk was even twenty times higher in the PiZZ genotype.

The study also investigated the effects of alpha-1 antitrypsin replacement therapy on the liver. Two groups of PiZZ patients were formed: those receiving (275) and those not receiving (206) replacement therapy. Liver function tests, specifically AST, gamma-GT, and bilirubin, were slightly more favorable in the alpha-1 antitrypsin group compared to those not receiving this treatment. This may be explained by the anti-inflammatory effects of alpha-1 antitrypsin. FibroScan® results were also somewhat better in the replacement group, with values above 10 kilopascals only found in 111 TP3T of the replacement group compared to 161 TP3T of the untreated patients.

Results from relatives with PiMZ type

In the general German population, the PiMZ type is found in at least one in 50 people. The Alpha-1 Liver Study investigated whether this mutation promotes chronic liver disease. The liver function tests of individuals with PiMZ were intermediate between those of people with healthy Alpha-1 genetics (PiMM) and patients with the PiZZ type. A similar pattern was observed with liver stiffness, which was more frequently elevated in PiMZ than in PiMM subjects. The situation was even more unfavorable when individuals with PiMZ also had severe obesity. Obesity is considered a significant and, in principle, preventable risk factor for liver cirrhosis.

Other liver diseases and PiMZ type

Heavy alcohol consumption puts a strain on the liver, potentially leading to end-stage cirrhosis. The risk of developing cirrhosis is about five times higher in alcoholics with the PiMZ genotype. A similar pattern is observed in another very common liver disease, non-alcoholic fatty liver disease. Here, the risk of cirrhosis is seven times higher in individuals with the PiMZ genotype than in those with the normal PiMM genotype.

New therapeutic principle in clinical development

A completely new therapeutic approach is about to be tested in a clinical trial: siRNA-based treatment, or RNA interference. When proteins are produced in liver cells, the genetic information is transferred from the DNA to messenger RNA (mRNA). This is essentially a copy of the genetic material and a prerequisite for the synthesis of the respective protein in another part of the cell. Drugs that inhibit the reading of mRNA have now been approved. They work via artificially produced siRNA (small interfering RNA), which can thus effectively silence individual genes.
A siRNA-based treatment has now been developed specifically for alpha-1 antitrypsin deficiency. A phase II/III trial will begin in 2019 to demonstrate the safety, tolerability, and efficacy of the new substance. The trial is only suitable for a small number of patients: they must already have liver disease, but their lungs must still be relatively healthy, as their FEV1 must be above 65% of the predicted value. If lung function deteriorates acutely during an exacerbation of the condition in the study, participants not yet receiving alpha-1 antitrypsin replacement therapy will be given to them.
The study is being conducted in several countries with the aim of examining a total of 72 patients. In Germany, Aachen is the only center. The investigational drug is injected subcutaneously and is expected to be effective for two months. Liver biopsies will be performed during the clinical trial to obtain the most accurate information about liver health.
Those interested are invited to learn more about the study at the Alpha-1 Liver Center of the University Hospital Aachen.

Summary: Prof. Dr. med. Gratiana Steinkamp, as published in Alpha1 Journal 1-2019.