The liver is known for its ability to regenerate (see last issue’s cover story for more information). It can completely regrow itself even after two-thirds of its mass has been surgically removed. But damage from medications, alcohol abuse or obesity can eventually cause the liver to fail. Currently, the only effective treatment for end-stage liver disease is transplantation.
However, there is a dearth of organs available for transplantation. Patients may have to wait from 30 days to over five years to receive a liver for transplant in the U.S. Of the over 11,600 patients on the waiting list to receive a liver transplant in 2021, only a little over 9,200 received one.
But what if, instead of liver transplantation, there was a drug that could help the liver regenerate itself?
I am the founding director of the Pittsburgh Liver Research Center and run a lab studying liver regeneration and cancer. In our recently published research, my team and I found that activating a particular protein with a new medication can help accelerate regeneration and repair after severe liver injury or partial surgical removal in mice.
The liver performs over 500 key functions in your body, including producing proteins that carry fat through the body, converting excess glucose into glycogen for storage and breaking down toxins like ammonia, among others.
Liver cells, or hepatocytes, take on these many tasks by a divide-and-conquer strategy, also called zonation. This separates the liver into three zones with different tasks, and cells are directed to perform specialized functions by turning on specific genes active in each zone. However, exactly what controls the expression of these genes has been poorly understood.
Over the past two decades, my team and other labs have identified one group of 19 proteins called Wnts that play an important role in controlling liver function and regeneration. While researchers know that Wnt proteins help activate the repair process in damaged liver cells, which ones actually control zonation and regeneration, as well as their exact location in the liver, have been a mystery.
To identify these proteins and where they came from, my team and I used a new technology called molecular cartography to identify how strongly and where 100 liver function genes are active. We found that only two of 19 Wnt genes, Wnt2 and Wnt9b, were functionally present in the liver. We also found that Wnt2 and Wnt9b were located in the endothelial cells lining the blood vessels in zone 3 of the liver, an area that plays a role in a number of metabolic functions.
Eliminating the two Wnt genes from endothelial cells also completely stopped liver cell division, and thus regeneration…
To our surprise, eliminating these two Wnt genes resulted in all liver cells expressing only genes typically limited to zone 1, significantly limiting the liver’s overall function. This finding suggests that liver cells experience an ongoing push and pull in gene activation that can modify their functions, and Wnt is the master regulator of this process.
Eliminating the two Wnt genes from endothelial cells also completely stopped liver cell division, and thus regeneration, after partial surgical removal of the liver.
We then decided to test whether a new drug could help recover liver zonation and regeneration. This drug, an antibody called FL6.13, shares similar functions with Wnt proteins, including activating liver regeneration.
Over the course of two days, we gave this drug to mice that were genetically engineered to lack Wnt2 and Wnt9b in their liver endothelial cells. We found that the drug was able to nearly completely recover liver cell division and repair functions. Lastly, we wanted to test how well this drug worked to repair the liver after paracetamol overdose.
Paracetamol, or acetaminophen, is an over-the- counter medication commonly used to treat fever and pain. However, an overdose of paracetamol can cause severe liver damage. Without immediate medical attention, it can lead to liver failure and death. Paracetamol poisoning is one of the most common causes of severe liver injury requiring liver transplantation in the U.S. Despite this, there is currently only one medication available to treat it, and it is only able to prevent liver damage if taken shortly after overdose.
…one dose was able to decrease liver injury biomarkers … in the blood and reduce liver tissue death.
We tested our new drug on mice with liver damage from toxic doses of paracetamol. We found that one dose was able to decrease liver injury biomarkers—proteins the liver releases when injured— in the blood and reduce liver tissue death. These findings indicate that liver cell repair and tissue regeneration are occurring.
One way to address liver transplantation shortages is to improve treatments for liver diseases. While current medications can effectively cure hepatitis C, a viral infection that causes liver inflammation, other liver diseases haven’t seen the same progress.
Because very few effective treatments are available for illnesses like nonalcoholic fatty liver disease and alcoholic liver disease, many patients worsen and end up needing a liver transplant.
My team and I believe that improving the liver’s ability to repair itself could help circumvent the need for transplantation. Further study of drugs that promote liver regeneration may help curb the burden of liver disease worldwide.
– Satdarshan (Paul) Singh Monga, Professor of Pathology and Medicine, University of Pittsburgh
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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“It was a strange time. When they told me and my parents that I had non-A non-B hepatitis—that’s what hep C was called then—the nurses were all gowned up and wearing gloves and masks. I had never seen it before. It was a bit like COVID.”
After his diagnosis Jake was monitored regularly with liver function tests. His doctors explained that hep C might progress slowly and they would need to keep an eye on his liver health.
For quite a few years there was little change and I didn’t think much about it. Then in my mid-20s the doctors could see some small differences in my liver function tests. I had a transjugular liver biopsy and that showed a little bit of damage in my liver.”
But suddenly in his early 30s his liver health started deteriorating and at a rapid rate. This was some years before 2016, when the new highly successful DAA hep C therapies became available in Australia. He commenced triple therapy treatment with telaprevir, interferon and ribavirin but did not respond to treatment.
“That was really disappointing and I was very upset. The next year I had another biopsy and they told me that I had definitely developed cirrhosis. Things got really bad for me then. I felt horrible, tired and very anxious.”
With a combination of non-response to treatment and haemophilia, his options for clinical trials in Australia were very limited at the time. Desperate, he applied for clinical trials around the world and just as he was losing hope, he had a positive reply from a clinic in the USA. This was no ordinary situation. He persuaded the clinic he could take responsibility for himself and his health, his hospital in Australia provided all his clinical documentation, then he travelled to and from the USA to participate in the trial.
His hep C treatment was Harvoni (ledipasvir and sofosbuvir), one of the DAA therapies that are now widely available in Australia.
“I had one tablet a day for 12 weeks. Side effects? Some confusion and blurry vision, but my liver was in pretty bad shape so it might have been something else. And it all returned to normal as soon as I finished treatment. It was a piece of cake compared to interferon.”
When he received his results showing he had been cured of hep C, Jake was not surprised. “I already knew. I felt different. I felt good”
Even though his hep C has been cured, Jake had cirrhosis before treatment, which means he needs ongoing liver health monitoring.
“I have to have 6-monthly liver checkups because with cirrhosis I’m at an increased risk of cancer. I go to a liver clinic at the hospital to see a specialist – the same hospital as my Haemophilia Treatment Centre, just in case there are any issues with my haemophilia.”
Jake sees this as part of his routine care. He has some tests and a Fibroscan ultrasound, then follows up with an appointment with the specialist about a week later to discuss the results. With COVID, his specialist appointment is now via telehealth.
“It’s no big deal. As we get older, we need to be more careful of our body anyway. The liver function tests are normal blood tests—I just have them every 6 months, along with other regular blood tests I have, like cholesterol and blood sugar. And I can do them at the pathology unit at the weekend if I want to. The ultrasounds are at the hospital. They are painless, take 5 minutes.”
While it can involve time off work, Jake thought the effort was well worth it.
“I don’t think anyone likes to have health checks all the time, but it is definitely peace of mind. If they find something, they can act on it straight away. You don’t want to find out down the track when there is not much you can do.”
Since his hep C cure, Jake’s liver health has improved remarkably.
“I still have a bit of liver damage now, but it is not nearly as bad as before treatment. It’s amazing.
“Now that my liver is working better, everything is better. I have as much energy as when I was 21 years old. My moods are better. I don’t get itchy, I don’t get brain fog, I feel fine after a big meal.”
Jake has made changes to his lifestyle to take care of his health generally and thinks this has made a difference to his liver health recovery.
“I do help my body a lot. I haven’t drunk alcohol in 14 years. I don’t smoke. I walk a lot. I eat a Mediterranean diet and don’t eat much red meat or sugar.”
His message to others?
“We are living in different times. Anyone thinking about hep C treatment, just do it. Don’t hesitate. No one should live with hep C, especially these days. Treatment has never been easier.
“The damage to my liver happened so quickly. For years there was no change, then suddenly it went from bad to much worse. Make the effort to have treatment and follow up on your cirrhosis. Don’t give up. Life’s too short to take chances.”
This story was first published on the Haemophilia Foundation Australia website in July 2022, and is reprinted with permission.
]]>The Eliminate Hepatitis C Australia Partnership (EC Australia) was created in 2018 to bring together researchers, scientists, government, health services and community organisations to work toward eliminating hepatitis C as a public health threat in Australia by 2030 (see last issue for more).
The EC Australia “It’s Your Right” Health Promotion Campaign (IYR) aims to reduce the prevalence of hepatitis C amongst people who inject drugs by using peer engagement to increase access to hepatitis C testing and treatment. The campaign aims to shift perceptions about treatment and support people to prioritise treatment for hepatitis C.
The SA component of the IYR campaign was delivered between April and July in key metropolitan areas. Peer outreach focused on four areas: Adelaide and the inner suburbs, the northern suburbs, the southern suburbs and the western suburbs (including Port Adelaide). In each area trained IYR peers worked in pairs to talk to people who inject drugs about hep C and refer them to the local peer Clean Needle Program (CNP) and testing/treatment services. It’s Your Right merchandise (caps, tote bags, tourniquets) was used as an outreach engagement tool and given to people who inject drugs who engaged in HCV conversations with the IYR peers.
Hepatitis SA hep C peers conducted point-of-care testing for HCV at services in each of the four areas during the time that the IYR peers were undertaking outreach. Incentives were provided to people who inject drugs if they undertook testing after being referred by the IYR peers. Additional ‘bring a friend’ incentives were aimed at increasing the number of conversations about hepatitis C and the number of people accessing hep C testing or treatment. All participants testing positive were referred by the hep C peers to community-based viral hepatitis nurses for active follow-up.
The It’s Your Right campaign provided many opportunities for the CNP Peer Projects. The street/community-based outreach was a new way to engage with people who inject drugs, especially more marginalised injectors, and to facilitate increased access to hep C testing and treatment for our clients. Having CNP peers working with and supporting hep C peers provided an opportunity to work more closely across programs within Hepatitis SA. The campaign was also an opportunity to recruit and train more peer workers, including 2 Aboriginal peers which has led to increased engagement with Aboriginal people who inject drugs.
Some notable ‘It’s Your Right’ Health Promotion Campaign Successes:
In addition to the peer engagement component of the campaign, there was a series of posters encouraging people who inject drugs to get tested for hep C. The posters were placed in laneways, public areas, shopping centres and even on metro buses. There was good feedback about the posters, with people commenting on the bright colours as a welcome change from some of the usual hepatitis C health promotion resources. Most of the feedback related to the “Get Clear on Gear” poster which received positive feedback from everyone who commented on it.
For more information on hepatitis C testing and treatment, or to view video testimonials from people who have cleared hepatitis C through treatment, go to itsyourright.com.au.
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