Israelis discover gene responsible for liver disease

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.

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“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.”

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About Karin Kloosterman

Karin Kloosterman is an award-winning environment news publisher who founded Green Prophet ( to connect North Americans to issues that matter in the Middle East. She is the CEO of the Internet of Things startup flux, a company that is making social grow tools for urban farmers everywhere ( Karin can be reached at karin (at)
  • Maxine Silva

    Dear Ms Kloosterman,

    Thank you for your informative article; however after almost 40 years since the death of my 3 year old daughter from liver disease, focus is still on alcoholic cirrhosis. My child suffered from one of 100 identified liver disorders in children (Biliary Atresia). She died of the complications of cirrhosis, having nothing to do with alcohol or drugs.

    I know there are millions of people afflicted by alcoholic liver disease and billions affected by its consequences. Our biggest dilemma in dealing with this social problem is “Stigma.” Attitudes shape the framework of our actions and thus “Denial” persists.

    In your public position to impact and potentially change perceptions, perhaps you will consider writing about the little children and babies worldwide, who innocently die from the complications of liver disease. I am forever hopeful that science and medicine will ultimately save these little lives.

    It is the attention on the plight of children, that will push through the “veil of shame” so All who suffer can be helped.

    Respectfully, Maxine Turon Silva

    • Jenn

      No doubt any advances and treatments that are made from this kind of research will benefit a range of liver disease for young and old no matter the cause.

      I am sorry to hear about your loss. I am a mother myself and I can’t imagine the pain of losing a child.

    • hope4j

      I have primary billiary cirrosis which is not caused by drinking alcohol mine is caused by my immune system breaking down besides that i have sj’gons disease and idiopathic pulmonary fibrosis of the lungs and i am just thankful that this research is going i am 65yrs so it is too late for me but for future sufferers its looking good
      many thanks and my best wishes

  • Begin

    Yep, along with Maxine, me too agree, Karin writes always about, really useful innovation / findings as information for mankind !!!
    Thank you for your continuous efforts being a Green Prophet!!
    All the best!!!!!!!!!!!!!!

  • Patty Ann Smith

    People should be aware that anytime they are going to put alcohol or medicine in their body, they should “for their livers sake” make sure they never put those things into an empty liver.
    As far as children are concerned being born with a bad liver would be because their mother put something like alcohol or medication in her body on an empty liver when she was caring the baby.

  • Susan March

    Dear Ms. Kloosterman,

    I was shocked after reading your first sentence that one gene is the cause of all liver diseases.Alcohol is not the only reason for a person to contract a liver disease. In most cases there is no known reason for why a disease process shows up in the liver. It’s insensitive to suggest that alcohol plays a role in all diseases of the liver.

    I have a rare degenerative liver disease that isn’t caused by drinking alcohol. Unfortunately there are many liver diseases that just happen and the cause is unknown. I appreciate that research continues to focus on the liver and perhaps in my lifetime the cause of my disease process will be known and more importantly there will be a cure.

    Susan F. March

  • mscognizance

    Although alcohol is the main cause of liver damage, the article does mention over-eating and some drugs. More focus on this would have been helpful. Tylenol is very dangerous for the liver. Fatty liver is another great problem. I wonder how much environmental poisons are effecting our livers. Newborn babies are found to have traces of industrial chemicals and insecticides in their tissues.