Groundbreaking advance clears the way for future medications to better target a deadly problem.
After years of hunting, Dr. Rifaat Safadi and his team of Hadassah medical researchers in Jerusalem have found the gene that causes liver disease. This groundbreaking discovery paves the way for potential new treatments.
Safadi, an Arab-Israeli physician who heads the Liver Unit at Hadassah University Hospital in Ein-Karem, tells ISRAEL21c that while the gene, Neuroligin 4 (NLGN4), was already known to be involved in brain neuron communication, his team was the first in the world to identify NLGN4 in the immune system and liver.
“The gene is there and now the question is how much of it is being expressed, since an over-expression of this gene is affecting immune system modulation, or the immune control of fibrosis in the liver,” he explains.
In a healthy person, NLGN4 helps repair liver tissue when it gets damaged by daily abuses. But if the immune system is compromised by hepatitis, alcohol consumption, over-eating or the use of some medications, the gene overreacts and doesn’t work as well to prevent liver scarring. This increases the risk of cirrhosis of the liver — the final phase of advanced liver disease.
Ordinarily, Safadi adds, the immune system’s “natural killer” (NK) cells do the work of keeping a stressed liver scar-free. But once cirrhosis develops, NLGN4 inhibits these NK cells.
“Everyone has the gene,” says Safadi, “whether it’s over-expressed or not. Our approach is how to target the over-expression and to reduce this expression to control the fibrosis.”
In the study, Safadi and his team took blood samples from hospital patients to look at their NK cells. One group had cirrhosis of the liver, while the other was a control group for comparison purposes.
Hadassah’s Hadasit Technology Transfer Company has patented Neuroligin 4 and Safadi plans on working toward creating a drug based on the new knowledge, which was reported at an American Association for the Study of Liver Diseases in Boston late last year.
Searching for a happy ending
Safadi believes the problem of alcoholism in Israel and worldwide is underestimated. “In my clinic [in Nazareth] I saw a large volume of alcoholic liver disease, with Christians coming in as often as Muslims and Jews,” he says. “We call it liver disease when we don’t find the cause, and most cases of this ‘cryptogenic liver disease’ is found in alcoholics.”
Even social drinkers are not immune to the effects of alcoholism and liver scarring, says Safadi. “Patients in our community, for various reasons, are underreporting their consumption. It’s only when you repeat the questions in different ways and see a patient over time and win his trust does the true story come out.”
His weekend work in the clinic propelled him to find a way to treat people suffering from cirrhosis of the liver. Safadi hopes to find a happier ending to the sad story of late-stage liver disease.
There are non-drug approaches to help a damaged liver heal, says Safadi, based on clinical experience: “Weaning from alcohol in the heavy drinker helps rehabilitate the immune system – and can even reverse cirrhosis in some cases,” he says.
“Yes, just stopping can help the liver heal. And this has a bigger effect — more than any drug that we can discover. If this is not the case, our drug will be targeting pathways to reduce the fibrosis tissue, and this is my niche.”