By HualinXMN – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=133759262
GLP1 agonists such as Ozempic (semaglutide) are associated with a reduced risk of developing cirrhosis and liver cancer in people with type 2 diabetes and chronic liver disease, according to a nationwide study from Karolinska Institutet published in the journal Gut.
GLP1 agonists reduce blood sugar levels and are mainly used to treat type 2 diabetes. Since the drug also reduces appetite, it is now increasingly used to treat obesity and has become a popular weight-loss drug.
Reduced risk of liver damage
Results from early clinical trials also suggest that GLP1 agonists may reduce the risk of liver damage. Therefore, researchers at Karolinska Institutet included all people in Sweden with chronic liver disease and type 2 diabetes in a register-based study. They then compared the risk of severe liver damage in those who were treated with GLP1 agonists and those who were not. The results show that those who took the drug for a long period of time had a lower risk of later developing more severe forms of liver disease such as cirrhosis and liver cancer.
According to the researchers, this suggests that GLP1 agonists could be an effective treatment to avoid severe liver disease in people with concurrent type 2 diabetes.
“Fatty liver disease is estimated to affect up to one in five people in Sweden, many of whom have type 2 diabetes, and about one in twenty develop severe liver disease,” says first author Axel Wester, assistant professor at the Department of Medicine, Huddinge, Karolinska Institutet. “Our findings are interesting because there are currently no approved drugs to reduce this risk.”
Many of the people in the study stopped taking GLP1 agonists, resulting in a lack of protective effect. However, those who continued taking their medication over a ten-year period were half as likely to develop severe liver disease.
Clinical trials needed for confirmation
“The results need to be confirmed in clinical trials, but it will take many years for these studies to be completed,” says Axel Wester. “Therefore, we use existing registry data to try to say something about the effect of the drugs before that.”
A limitation of the method is that it is not possible to control for factors for which there is no data, such as blood tests to describe the severity of liver disease in more detail. However, the researchers have recently built a new database called HERALD where they have access to blood samples from patients in Region Stockholm.
“As a next step, we will investigate the effect of GLP1 agonists in this database,” says the study’s last author Hannes Hagström, consultant in hepatology at the Karolinska University Hospital and adjunct professor at the Department of Medicine, Huddinge, Karolinska Institutet. “If we get similar results, it would further strengthen the hypothesis that GLP1 agonists can be used to reduce the risk of severe liver disease.”
The research was mainly funded by Region Stockholm (CIMED), the Swedish Research Council and the Swedish Cancer Society. Hannes Hagström’s research group has received funding from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk and Pfizer, although no industry-supported funding was obtained for this specific study.
People in South Africa who fall ill with tuberculosis (TB) often also have other health issues. HIV, which drives much of the TB epidemic in South Africa, is the most obvious co-infection, but people who fall ill with TB are also more likely to have diabetes and mental health problems than the general public.
Another issue that is often mentioned at conferences and in journal articles, but that doesn’t often make the headlines, is the complex set of links between TB and liver problems. With the World Health Organization estimating that in the region of 300 000 people fall ill with TB in South Africa every year, the scale of the issue is likely to be substantial, although we do not have particularly good data on liver problems in South Africa, and even less so on people experiencing TB and liver problems together.
Complex interactions
Broadly speaking, the link between TB and the liver can be divided into two categories. First, there are the liver-related side effects of some TB treatments, and second, there is the interaction between TB and liver conditions such as viral hepatitis. In some cases, TB itself can also cause liver problems directly.
Start with hepatitis. Dr Louisa Dunn, Think TB Provincial TB Technical Lead in KwaZulu-Natal, explains that hepatitis is a general term meaning inflammation of the liver. She says that there are many causes of hepatitis, such as infections, alcohol, or an overdose of certain medications. There is also autoimmune hepatitis, where a person’s own immune system is attacking the liver. “Even lifestyle can cause inflammation in the liver from a build-up of fatty tissue, which is more common in people who are overweight and obese,” she says.
Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are thought to cause significant illness and death in South Africa. According to a study published in 2022, over 1.9 million people in South Africa are living with chronic HBV infection – earlier research put the number at 3.5 million. HBV can be treated and there is an effective childhood vaccine for it that has been used in South Africa since 1995.
Estimates for HCV are less certain than for HBV – an estimate of 400 000 chronic infections was quoted in an HBV and HCV investment case for South Africa. Highly effective cures for HCV infection have been developed over the last decade, although access to these cures remains limited. The Department of Health published viral hepatitis treatment guidelines in December 2019.
Given these numbers, some people in South Africa would simply, by chance, get both TB and hepatitis. But since there are common risk factors, co-infection will be higher than what one would expect purely through chance. HIV infection, for example, increases both a person’s risk of TB and HCV.
“There is no data from South Africa about viral hepatitis and TB co-infection that I am aware of,” says Dr Andrew Scheibe, a Technical Advisor for TB HIV Care and an infectious disease specialist at the University of Pretoria. He points out that people who use drugs and other groups of people who are marginalised, including people experiencing homelessness or people in prison, are at increased risk for these co-infections. The risk of HCV transmission is particularly high when people who inject drugs share needles.
In addition, as Dunn points out, TB itself can also cause hepatitis.
Hepatotoxicity
The picture is further complicated by the fact that several of the medicines used to cure TB have liver-related side effects. Drug-sensitive TB is treated with a combination of four different medicines, while drug-resistant TB is treated with anything from three to eight different medicines.
“Medications used to treat both drug-sensitive and drug-resistant TB can cause hepatitis through drug-induced liver toxicity (hepatotoxicity),” says Dunn. “The presence of other risk factors may further increase the risk of hepatitis in TB patients. These risk factors could be alcohol use, older age, malnutrition, co-infection with HIV or viral Hepatitis B, and taking other potentially hepatotoxic drugs with TB treatment.”
Wieda Human, project coordinator and communications officer at TB advocacy group TB Proof says 3 to 28% of people with TB may experience hepatotoxicity and other side effects. “Those who are already infected with the hepatitis B infection are at an increased risk for hepatotoxicity,” she says.
She refers to a study done in Ethiopia that found having hepatitis B and hepatitis C infection made having TB disease more severe. “This study also found that people with TB who have hazardous alcohol use have a 1.5 times increased risk of developing hepatitis C,” says Human.
What it means for treatment
Dunn says although it is less straightforward to treat a person with TB and hepatitis than a person with just TB, it is important to understand treatment is still available. “It involves establishing the cause for hepatitis and treating this where possible, for instance, treating a viral hepatitis [and TB] co-infection at the same time or [providing] support to reduce alcohol intake. It may involve closer monitoring and follow-up, changes to medications, including stopping treatments either permanently or temporarily, and using alternative more ‘liver-friendly’ treatment regimens,” she says.
“If the hepatitis is stable, then TB can be treated,” Scheibe says. He explains hepatitis B requires long-term treatment (there is no cure), while hepatitis C can be cured with direct-acting antivirals (recently registered in SA, but not yet on the Government Essential Medicines List, so not easily available in the public sector). He says HCV treatment may be delayed until the TB is cured.
No routine screening
South Africa’s National Strategic Plan for HIV, TB, and STIs 2023-2028 under Goal 2 sets out to reduce viral hepatitis morbidity through scale-up of prevention, diagnostic testing, and treatment. However, according to Dunn, screening for viral hepatitis infections, such as HBV, is not part of the current drug-sensitive or drug-resistant TB guidelines.
But she says everyone should be assessed for symptoms and risk factors for liver disease at the start of TB treatment – a sentiment Scheibe shares. According to them, these screenings are however performed at diagnosis of HIV infection before a person is commenced on antiretroviral treatment for HIV, as chronic hepatitis B infection has specific implications for HIV treatment.
“During [TB] treatment, it is critical that clinicians assess people for signs and symptoms that may suggest hepatitis at each visit and educate them on recognising these side effects as well,” says Dunn. “This includes loss of appetite, feeling tired and unwell, nausea, vomiting, abdominal pains, yellowing of the eyes and skin, and darkening of urine.”
Treatment guidelines for drug-induced liver injury are available here. The guidelines focus on the management of suspected drug-induced rash, kidney injury, and liver injury for patients on TB treatment and or antiretroviral treatment.
Scheibe adds that people at high risk for HCV should receive TB screening regularly due to potential exposure to TB (eg if living in closed settings with many people in contexts of high TB prevalence and /or with HIV co-infection).
Research published in the Proceedings of the National Academy of Sciences has shown for the first time that the effects of Alagille syndrome, an incurable genetic disorder that affects the liver, could be reversed with a single drug. The study has the potential to transform treatment for this rare disease and may also have implications for more common diseases.
More than 4000 babies each year are born with Alagille syndrome Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with a wide variety of clinical manifestations. The clinical manifestations are variable, even within the same family, and commonly include hepatic (cholestasis, characterised by bile duct paucity on liver biopsy), cardiac (primarily involving the pulmonary arteries), skeletal (butterfly vertebrae), ophthalmologic (posterior embryotoxon), and facial abnormalities.
“Alagille syndrome is widely considered an incurable disease, but we believe we’re on the way to changing that,” says Associate Professor Duc Dong, PhD, who led the study. “We aim to advance this drug into clinical trials, and our results demonstrate its effectiveness for the first time.”
Children with ALGS frequently require a liver transplant, but donor livers are limited, and not all children with ALGS qualify. Without a transplant, the disease has a 75% mortality rate by late adolescence.
“Duc and his team continue to do thrilling research on Alagille syndrome, and these breakthroughs certainly offer hope for families living with this very complicated and complex disorder,” says Roberta Smith, CNMT, president of the Alagille Syndrome Alliance. “We have been longtime supporters of Duc’s work and have come to know him as a driven, dedicated scientist who is passionate about moving the needle one step closer toward a cure.”
Their new drug, called NoRA1, activates the Notch pathway, a cell-to-cell signaling system present in nearly all animals. Notch signaling helps orchestrate fundamental biological processes and plays a role in many diseases in addition to Alagille syndrome. In children with Alagille syndrome, a genetic mutation causes a reduction in Notch signaling, which results in poor liver duct growth and regeneration.
The researchers found that in animals with mutations in the same gene affected in ALGS, NoRA1 increases Notch signaling and triggers duct cells to regenerate and repopulate in the liver, reversing liver damage and increasing survival.
“The liver is well known for its great capacity to regenerate, but this doesn’t happen in most children with Alagille syndrome because of compromised Notch signaling,” says first author Chengjian Zhao, a postdoctoral researcher in Dong’s lab. “Our research suggests that nudging the Notch pathway up with a drug could be enough to restore the liver’s normal regenerative potential.”
The researchers are currently testing the drug on lab-grown liver orgnelles cultured made with stem cells derived from the cells of ALGS patients.
“Instead of forcing the cells to do something unusual, we are just encouraging a natural regenerative process to occur, so I’m optimistic that this will be an effective therapeutic for Alagille syndrome,” adds Dong.
Researchers say that leprosy may hold to the key to safe and effective organ regeneration, after discovering that leprosy can double the size of livers in armadillos by stimulating normal, healthy growth.
Their findings, published in the journal Cell Reports, reveal a previously unknown interaction of the leprosy bacterium with its host, in this study, an armadillo – the only one known one besides humans that the disease may manifest in.
The researchers found that leprosy appears to rewind the developmental clock of liver cells, effectively reprogramming them to be in an ‘adolescent’ state.
Regenerative medicine aims for ‘grown to order’ organs to replace those damaged by disease or age, but organ development is an extremely complex process which takes place in vivo and so far only limited progress has been made using in vitro models. The liver, a highly resilient organ, stops regenerating once it reaches its original size, making it difficult to study regeneration pathways.
Leprosy, also referred to as Hansen disease, is a chronic granulomatous infection generally caused by Mycobacterium leprae and Mycobacterium lepromatosis, both of which primarily affect the skin and peripheral nerves. It also has the ability to convert body tissues from one type to another.
Researchers infected four cloned armadillos with the bacteria, and observed the growth of their livers. The bacteria enlarged the liver, basically give themselves more room – and this was accomplished in a way that left the livers perfectly functional and healthy.
The researchers suggest that, as with other body tissues, the bacteria-induced partial reprogramming also works in adult liver in vivo, turning hepatocytes into liver progenitor-like cells leading to proliferation and subsequent re-differentiation in the microenvironment created by the bacteria.
Prof Anura Rambukkana, from the University of Edinburgh’s centre for regenerative medicine described the discover as “completely unexpected”.
“It is kind of mind-blowing,” Prof Rambukkana told the BBC. “How do they do that? There is no cell therapy that can do that.”
Using an innovative 3D imaging technology, researchers at Karolinska Institutet have discovered that a part of the liver’s autonomic nervous system undergoes severe degeneration in non-alcoholic fatty liver disease.
The study showed that the degeneration of nerves is correlated with the severity of liver pathology. The findings are being published in the journal Science Advances.
With a global prevalence of about 25 percent, non-alcoholic fatty liver disease is the most common hepatic disorder. Approximately one third of all fatty liver cases progress to steatohepatitis, a severe disease seriously affecting the entire metabolism.
In the current paper, researchers explore the nervous system in fatty liver using volume immuno-imaging and light sheet microscopy ― a novel imaging technique, which together offers large-scale 3D visualisation with cellular resolution. According to the study, this technology can reveal even early, minor or hidden structural impairments of the liver.
“Now we know that nerves in the liver have multiple subtle regulatory roles” says Csaba Adori, researcher at the Department of Neuroscience, who led the study. “Their role, however, may be more essential during the fight-or-flight response or when subjected to metabolic challenges. Degeneration of liver sympathetic nerves and abnormal operation of the remaining nerve fibres in the fatty liver could compromise all these functions, which may contribute to further aggravation of the disease, as part of a vicious cycle.”
According to the study, changes in liver innervation are already underway in the early stages of fatty liver disease. As it progresses to more severe steatohepatitis, these impairments become a significant degradation of the nerves. The nerve pathology is also similar in mouse models of fatty liver and in human fatty liver samples. The team hopes this will open new avenues for the treatment of steatohepatitis and portal hypertension, through targeting the liver sympathetic nervous system.
Japanese researchers have come up with a new approach that could revolutionise the treatment and prevention of liver disease damage and possibly regenerate liver scarring.
This novel strategy involves small extracellular vesicles (sEVs), which are lipid-enclosed particles that are naturally released from a cell. The ones used in this study derived from interferon-γ (IFN-γ) pre-conditioned MSCs (γ-sEVs).
Cirrhosis (scarring of the liver) and other chronic liver diseases result in up to 2 million deaths reported annually around the world, these in turn account for approximately 3.5% of annual deaths globally. As the only treatment for clinically advanced cirrhosis liver transplantation, targeted therapies for modulating fibrosis and aiding tissue regeneration. The ability to control fibrosis–the growth of fibrous tissue in response to damage– is often lost in livers under advanced cirrhosis. The research builds upon this.
One of the most popular approaches is cell therapy, where mesenchymal stromal cells (MSCs) and macrophages have shown the potential to reduce liver fibrosis. MSCs are able to transform into a number of different cells. They are cost-effective, being available not only from bone marrow, but also from medical waste such as umbilical cord tissue, adipose (fatty) tissue, and dental pulp.
Apart from the ease of availability, MSCs can also be lab-grown. MSCs don’t replace tissue but instead have been shown to be medical signaling cells that indirectly produce cytokines, chemokines, growth factors, and exosomes that are crucial for repairing and regenerating damaged tissue.
Previous research showed that MSCs have anti-inflammatory, anti-fibrotic, and anti-oxidative effects through these humoural factors. MSCs also have lower potential for provoking an immune response and therefore rejection, enabling their use in both within the same individual and another.
In a series of experimental mice studies, researchers pre-conditioned fat extracellular vesicles with interferon gamma (IFN-γ), an important immune system signaller. They showed that this increases the number of anti-inflammatory macrophages, which are the key players in tissue repair, reducing fibrosis and promoting tissue regeneration.
They reported that both MSCs derived from fatty tissue (AD-MSC-sEVs) and AD-MSC-γ-sEVs can boost macrophage motility and phagocytic activity. In addition, they also show that AD-MSC-γ- sEVs can effectively control inflammation and fibrosis in mice with cirrhosis.
They found thatAD-MSC-derived sEVs can affect the shape and function of macrophages, effectively recruiting them into damaged areas to initiate tissue repair.
In an interview, researcher Dr Atsunori Tsuchiya at Niigata University, explained that, “Both mesenchymal stromal cells and macrophages are reported to have therapeutic effects for liver cirrhosis, however relationship of both cells and mechanisms of action was not clear. We challenged this problem.”
He continued, “We found the important fact that extracellular vesicles from interferon-γ can induce the tissue repair macrophages, which can regress fibrosis and promote liver regeneration effectively.”
Dr Suguru Takeuchi, another of the researchers at Niigata University, concurred: “In our previous study, we reported that intravenous administration of mesenchymal stromal cells migrated to the lung, can work as ‘conducting cells’ and affect to macrophages ‘working cells’ in the liver.
“In this study we first elucidated that extracellular vesicles from mesenchymal stromal cells are key molecules to affect the macrophages.”
This study, which complements macrophage therapy, holds potential as a strategy for treating liver diseases using small extracellular vesicles pre-conditioned with IFN-γ. However, further development is needed, as well as uncovering the mechanisms by which they increase Treg cell count.
“Our results showed that modified extracellular vesicles can become a new therapeutic strategy for liver cirrhosis,” said Professor Shuji Terai, Niigata University.
Rates of alcoholic liver disease are skyrocketing in young women, doctors in the US have warned. Much of it has to do with added pressures on women in the pandemic.
Alcoholic liver disease — including milder fatty liver and the permanent scarring of cirrhosis, as well as alcoholic hepatitis — are up 30% over the last year at the University of Michigan’s health system, said Dr Jessica Mellinger, a liver specialist there. Severe liver disease and cirrhosis can see survival rates as low as 10%.
The route by which liver disease develops varies according to the individual, although obesity, genetics and underlying health conditions play a role. Moderate consumption of alcohol, a glass or two of wine daily, is unlikely to contribute to it.
However, Dr Mellinger says that along with her colleagues, she has seen alcohol consumption edging upward, to a bottle of wine per day which results in increased risk of serious liver disease.
Since the beginning of the pandemic, no data on overall increases in serious alcoholic liver disease has yet been compiled by The Centers for Disease Control and Prevention. But, Dr Mellinger said, “in my conversations with my colleagues at other institutions, everybody is saying the same thing: ‘Yep, it’s astronomical. It’s just gone off the charts.’ “
The age demographic is also changing. “We’re seeing kids in their late 20s and early 30s with a disease that we previously thought was kind of exclusive to middle age,” she said.
The pressures of the COVID pandemic are partly to blame, and in many cases the extra burden is falling on women – who are already more susceptible to alcoholbecause they have a smaller water volume to distribute alcohol into and their bodies do less ‘first pass’ metabolism of alcohol in the stomach. Popular culture and advertising also encourages women to drink.
Psychological factors such as eating disorders and trauma from sexual abuse also fuel the disease.
“Whether this is early life sexual trauma or they are in a recent or ongoing abusive relationship, we see this link very, very closely,” said psychiatrist Dr Scott Winder, a clinical associate professor at the University of Michigan who treats liver disease patients. “Just the sheer amount of trauma is really, really tragic.”
The lack of overlap between the various fields in this complex relationship results in what he calls a “tragic gap”.
“The cultures of hepatology and the cultures of psychology and psychiatry are very disparate; we see patients very differently,” so physicians aren’t coordinating care, even when they should, he said.
Advanced liver disease may leave no other recourse than a liver transplant. “Unfortunately, transplantation is finite,” said Dr Haripriya Maddur, a hepatologist at Northwestern University. “There aren’t enough organs to go around. What it unfortunately means is that many of these young people may not survive, and die very young — in their 20s and 30s. It’s horrific.”
Some people such as Jessica Duena, a teacher who was diagnosed with alcoholic hepatitis at 34, and was hospitalised several times following the death of her boyfriend from heroin, have managed to turn the disease around and are encouraging others to do the same.
She wrote about her long-held secret in the Louisville Courier-Journal: “I’m Jessica, I’m the 2019 Kentucky State Teacher of the Year, I’m an alcoholic and I’ve been suffering in silence for years.”
She received hundreds of responses, mostly women like herself who were in similar circumstances.
“What I’ve noticed is quite a few of the women, typically, they were either educators, they were moms or they happened to be nurses or attorneys,” Duenas said. They poured their hearts out about the crushing and constant stress of kids, work and home life.
They also complained of the pressures outside the home. “Imagine being a teacher who gets evaluated on how your students do, given the situation today,” Duenas says. “I mean, that makes me want to drink for them, you know — like that’s a terrible pressure to be under.”
Duenas has started writing about the stories of such people who reach out to her on her website, www.bottomlesstosober.com.
