07.03.2024 - By examining liver samples from 116 deceased people with severe mental illness, researchers from the Department of Forensic Medicine show that smoking, overweight and alcohol abuse can play a decisive role in how well - or poorly - medicine works for the individual patient.
It is already known in research circles that an unhealthy lifestyle affects the body's enzyme levels and thus the ability to break down medication.
But a study from the Department of Forensic Medicine at Aarhus University has now shed light on how much lifestyle matters. Liver samples from 116 deceased mentally ill people have been examined - and crucially, a large proportion of the deceased were smokers, alcoholics and/or severely overweight.
By examining the amounts of enzyme expressed in the liver of the deceased, researchers can say something about how good or poor the deceased was at breaking down important medications.
"People suffering from serious mental illness have a life expectancy that is about 20 years lower than the rest of the population. There are several reasons for this - among other things, mentally ill people more often commit suicide, but they also have an increased incidence of lifestyle-related factors such as diabetes, obesity, smoking and alcohol and substance abuse," explains cand.scient. and PhD in health science Kata Wolff Pedersen, who is behind the study.
"It is exciting to look at how lifestyle affects the amount of drug-breaking enzymes in the body, because a change in the amount of enzyme can reduce the effectiveness of medication that this group of patients need," she says.
Alcohol and smoking increase medication breakdown The study from the Department of Forensic Medicine shows that smokers have twice as much of a particular drug-breaking enzyme (CYP1A2) than non-smokers. This means that smokers break down certain forms of medication (e.g. antipsychotic medication) faster and thereby theoretically have a greater risk of being mistreated.
"We are the first to show at the protein level that the enzyme level in smokers increases because simply more enzyme is expressed in the body," says Kata Wolff Pedersen.
The liver tissue was collected during forensic autopsies. A full toxicological analysis was then performed crossed with information about e.g. the deceased's alcohol and smoking history based on statements from either the police, relatives or general practitioner in the autopsy report.
On this basis, Kata Wolff Pedersen concluded that the level of the enzyme CYP2E1 among people with alcohol abuse was about 30% higher compared to people without known alcohol consumption.
"40% of the deceased included in our study are registered as alcoholics. This is an interesting group because they have a special lifestyle. When we have so many individuals, we can prove that alcohol abuse increases the amount of enzymes in the body," says the researcher.
"This means that standard doses of medication may work worse in a significant proportion of the group of people we have examined," says Kata Wolff Pedersen - and this is certainly not unimportant, she explains.
Overweight gives a low level of another enzyme It is rare for researchers to gain access to liver samples from such large groups of people. Studies of enzyme levels are normally conducted on liver microsomes in test tubes or through animal experiments. Since the samples in this study come from identifiable humans, it verifies that lifestyle factors - also overweight - play a role.
However, being overweight makes a difference to an important enzyme with the opposite effect. The study shows that people with a very high BMI produce significantly less amounts of the enzyme CYP3A4 - in fact they have only half as much enzyme in their body as normal weight people. This can mean that they break down medication too slowly and may experience side effects. CYP3A4 is involved in the metabolism of a wide range of important drugs, and therefore this could be significant in that overweight individuals do not receive the right dosage and potentially become mistreated.
"40% of the individuals in the study died from poisoning from a mixture of medication and intoxicants. But we cannot show that the poisoning was due to too little enzyme, as most substances are broken down by multiple different enzymes. You would have to be unlucky to die due to changed enzyme levels," explains Kata Wolff Pedersen.
Pig livers in the fridge The study also includes liver samples from deceased pigs, and Kata Wolff Pedersen has used them to establish that the enzyme levels after two days at room temperature are the same as in a fresh pig's liver. If the liver is refrigerated, the levels remain the same for a whole week.
This is good news for researchers interested in enzyme levels.
"We are the first to show that tissue from deceased individuals can be used to examine the levels of drug-metabolizing enzymes. This makes it significantly easier to obtain material in a field where it is otherwise virtually impossible to procure enough liver biopsies," she says.
In summary:
The study is part of the research project Survive, which through autopsies examines excess mortality among mentally ill people in collaboration between the three forensic institutes in Copenhagen, Odense and Aarhus as well as a number of other collaborators from the healthcare system.The study uses human post-mortem liver tissue to investigate protein levels in a seriously mentally ill population.The project was approved by the National Committee on Health Research Ethics, and the deceased individuals were only included in the study if informed consent was given by the relatives. Read more in the scientific article: https://dmd.aspetjournals.org/content/51/9/1169.long