What happens to liver cells when too much fat accumulates? What are the risks ? Where is the research? These are all questions answered by Professor Pierre-Emmanuel Rautou, hepatologist responsible for the “Role of vessels in liver diseases” team at the Inflammation Research Center in Paris, and Professor of hepatology at Beaujon Hospital. .
Why doctor: 20% of the French population has fatty liver today. Have you also, in your practice, noticed an increase in cases of non-alcoholic steatohepatitis (NASH) in recent years?
Professor Pierre-Emmanuel Rautou: Yes, and obviously! There is an undeniable increase in the number of cases worldwide linked to the epidemic of diabetes and obesity. The number of patients suffering from NASH (or MASH now) is completely exploding, at all stages of severity. The majority of people I see are people aged 40 to 50, patients who have fatty liver and fibrosis lesions, in other words cirrhosis in the liver; and then also patients at the more advanced stage, with complications from their cirrhosis, this is what we call decompensation. I also see more and more people with a cofactor, that is to say another disease associated with NASH. In this regard, the study that we have just published a few months ago as part of the RHU Quid NASH, which included 500 patients with diabetes, showed that 30% of them had cirrhosis or pre-cirrhosis while remaining completely asymptomatic. However, diabetes is extremely common, but the risk of cirrhosis is often unknown among patients. There is also an explosion in childhood obesity, leading to cases of NASH in young adults.
NASH: “it takes around 20 years to reach the stage of cirrhosis”
What happens in the liver cells when we talk about non-alcoholic steatohepatitis? How do we go from the stage of steatosis to that of fibrosis, then to cirrhosis?
The basis is the fat which accumulates in the hepatocytes, the liver cells. One thing that is clear is that in some individuals who have fatty liver, not all, there will be lipotoxicity – lipid toxicity – one of the drivers of local stress. This creates an environment of inflammation which will locally attract immune cells and which will also modify other cells inside the liver: the endothelial cells which line the small vessels inside the organ, and stellate cells.
The endothelial cells of the liver are sensors, they will be activated under the effect of hepatocytes which are suffering but also by the effect of stimuli derived from the portal vein. It is the vein which runs through the entire digestive system and which empties into the liver. These endothelial cells are therefore the first in contact with this special blood which is very rich in nutrients derived from the digestive tract. It is also potentially rich in elements derived from visceral adipose tissue, therefore abdominal fat, and in insulin, because the pancreas drains into it and when you have diabetes or insulin resistance, there are insulin levels students. Finally, when there are bacteria in the intestine that are altered, small pieces also pass into this portal vein and therefore the endothelial cells of the liver see them arriving as well.
The third very important element in the cellular team of the liver, as mentioned previously, is the stellate cells. In a normal situation, they dilate or constrict the vessels inside the liver depending on variations in the flow arriving in the organ (because when we eat, the flow is greater, so the size of the vessels must be modulated). When exposed to stimuli derived from hepatocytes or endothelial cells of the liver, they change their phenotype and release fibrosis, which is the source of cirrhosis.
In summary, inflammatory activity in the liver sets the stage for fibrosis, which itself sets the stage for cirrhosis, which itself sets the stage for complications, namely liver cancer and decompensation.
How long does it take to go from non-alcoholic fatty liver disease to cirrhosis?
When you have an attack on the liver, whether it is alcohol, a hepatitis B or C virus, or even NASH, it takes around 20 years to reach the stage of cirrhosis. So if you start to be overweight at 25, cirrhosis occurs at 45.
Diagnosis: “Fib4 is a good marker for the treating physician”
As we said at the start of the interview, 1 in 5 French people have fatty liver… But as the disease remains asymptomatic for a long time, a good number do not know it! What should be put in place to improve diagnosis?
Today, we have more tools than a number of years ago that allow us to better identify patients, but the problem is how do we use these tools? Because as we are dealing with a disease that affects 20% of the population, we would have to set up a funnel effect with very simple and inexpensive tools for the treating doctor, and then refine it as we progress. arrives with the specialist.
Fib4, which includes age, platelets and transaminases, AST and ALT, is a good marker for the attending physician because it allows with a simple blood test to say that there is no problem. And if this is not the case, if the result is too high, we refine it, we go further. We do either the Fibroscan or patented fibrosis tests such as the FibroTest or the Fibrometer which also take blood samples.
The biopsy is reserved for the most advanced cases, or when there is doubt about a diagnosis, that is to say when there are several causes and we do not really know. But it is less common because it is a more invasive procedure with a one-day hospitalization, and although the risks are minimal, they are still greater than a simple ultrasound.
Decompensated cirrhosis: the median survival of patients is 2 years
What is the life expectancy of a person with cirrhosis?
As a general rule in medicine, it is better to treat diseases early rather than later… If we reach the stage of cirrhosis with complications, such as liver cancer, digestive hemorrhage or even ascites in the stomach, this can endanger the patient’s vital prognosis. The median survival of a patient with asymptomatic cirrhosis is 10 years, decompensated cirrhosis, therefore with symptoms, is 2 years. So obviously it’s better to treat people when they are asymptomatic than when problems start to occur. A specificity of the liver is its capacity for reversion, so if the fibrosis is not too advanced, it can regress. This is not the case for all patients, but the sooner we stop the causative factor, the more fibrosis can regress and the more problems we can avoid. Note that cirrhosis causes around 10,000 deaths per year in France, and NASH is today the second cause of cirrhosis in the country.
With your research team, you are very interested in liver endothelial cells, why?
For the moment there are no drugs that act specifically on liver endothelial cells, so it is attractive to be interested in it because it is a completely new avenue.
We focus on these cells because they sense different signals and pass messages. If they are healthy, they protect their environment, and if they are less healthy, they allow fibrosis to appear. In fact, they are a bit like guardians of liver health! So being able to leave them or restore them to good health is a way of protecting the liver in general.
More precisely, we are interested in two aspects: the biomarker aspect, that is to say finding a way to know their health by a simple blood test, without having to do a liver biopsy; and on the other hand, find a way to restore them to health, because this would put the liver in a good direction in terms of its condition and reversion of fibrosis.