About Liver Failure

Liver Failure

Are there stem cell therapies available for liver failure?

To our knowledge, no stem cell therapy has received Health Canada or U.S. Food and Drug Administration approval for liver failure treatment at this time. Patients who are researching their options may come across companies with websites or materials that say otherwise and offer fee-based stem cell treatments for curing this disease. Many of these claims are not supported by sound scientific evidence and patients considering these therapies are encouraged to review some of the links below before making crucial decisions about their treatment plan. However, the field of research is fast-moving and work underway today may uncover new possibilities for more effective treatments tomorrow. Therefore, is is important to keep asking questions and to continue seeking advice from qualified experts..

For the latest developments read our blog entries here.

For more about stem cell clinical trials for liver failure click here.  (For printed version: http://1.usa.gov/1MJZ7mG)

How close are we? What do we know about liver failure?

  • The liver is critical for sustaining life. It metabolizes nutrients, removes waste products, filters toxic substances and drugs, maintains the levels of blood sugar, fat and hormones, and participates in immune responses.
  • The liver is the largest solid organ and the biggest reservoir of blood in the body.
  • Cells called hepatocytes make up the bulk of the liver and perform most of the critical functions, but their short life-span (150 days) requires the liver to constantly regenerate itself to remain healthy.
  • There are over 100 different kinds of liver diseases and many causes, including alcohol consumption, viruses, obesity, genetics, autoimmune diseases, drugs, toxins and cancer.
  • Liver failure can be the result of an acute health condition that develops in a matter of days or a chronic condition that evolves slowly over time.
  • Causes of acute liver failure include viral hepatitis (in adults) or acetaminophen toxicity, metabolic disorders and autoimmune disease (in children). Chronic liver disease is most often caused by an obstruction in the tubes that connect the gall bladder to the liver (in children) or alcohol and hepatitis C (in adults). ‘Fatty’ liver, caused by obesity and high triglycerides, is also an emerging cause of liver failure in adults.
  • Transplantation is the only effective treatment for liver failure, but the demand is so high that many people die with end-stage liver failure die while waiting for a donor organ.

How can stem cells play a part?

The liver is a very hardy organ that can withstand a great deal of abuse and still continue to function. But when the liver reaches a state of ‘failure,’ the damage is irreversible and its ability to function is diminished beyond repair. Currently, the only life-saving treatment is a liver transplant but donor organs are in short supply. Using stem cells to treat liver failure is still very much at the experimental stage but the possibility of harnessing stem cells to churn out limitless numbers of hepatocytes for transplant therapy is driving the field forward. As of March 2013, mouse liver stem cells have been successfully identified and grown in the laboratory but this is not the case with their human counterparts. As researchers work towards that goal they are also investigating whether stem cells from other tissue sources can be used to treat various types of liver failure.

Are there lots of groups working on developing a stem cell therapy?

There are many research teams around the globe working to develop stem cell therapies for liver failure. Their common purpose is to identify which stem cells are best suited for the job, how to coax them into becoming hepatocytes, and the large scale lab methods required for ramping up the production of stem cells and liver cells.

The challenges associated with these goals are considerable. For example, perfecting the methods to scale-up production of hepatocytes from stem cells is a difficult but necessary step because vast numbers of cells are required for transplants to be effective and for testing drugs and experimental models of liver disease.

In addition, although a number of different methods for transplanting stem cells or the cells they make (progeny) into the liver have been tested in humans – via the portal vein, hepatic artery or splenic artery – the ideal one has yet to be identified. High pressure in the arteries prevents the stem cells from successfully engrafting into the liver, and in patients with cirrhosis of the liver there can be a strange reversal of flow in the portal vein, re-routing transplanted cells to the spleen rather than to the liver.

Better cell storage is also a priority because hepatocytes cannot yet be maintained for a long time in culture before they lose the ability to function normally. Safety, engraftment and functionality are also key issues that will need more work before the full potential of using stem cells to treat end-stage liver failure can be achieved.

Stem cell research for liver disease continues to unfold in a number of different directions and some of the successful results are being translated into early Phase 1 and 2 clinical trials. The majority of these are testing the safety and/or effectiveness of bone marrow stem cells for alleviating the damage associated with liver cirrhosis, liver scarring due to injury, or liver cancer.

What research is underway?

Before basic stem cell research can be translated into the clinic for patients, it must first be rigorously tested and validated. For liver failure, this involves transplanting stem cells into animal models of liver disease to test if liver function can be restored and inflammation reduced. The main types of adult stem cells being considered are bone marrow stem cells, mesenchymal stem cells, and pluripotent stem cells

The road to finding a stem cell therapy for liver disease is paved with many challenges that will take time to overcome. But the wealth of information generated from labs around the globe is converging to help with the transition from basic research to the clinic. As researchers continue to grapple with the challenges, they are keeping their eyes firmly fixed on the target of using stem cells to regenerate the liver, reduce the levels of inflammation, and alleviate the shortage of livers for transplantation.

Current research using bone marrow stem cells

As far back as 2000, researchers showed that hepatocytes could grow in the body from non-liver cell sources. This phenomenon, called transdifferentiation, was verified in female patients given bone marrow transplants from male donors: the new liver cells in the female patients could be traced to the male donor bone marrow cells.

Today, autologous (from the patient) bone marrow stem cells are the only stem cells that have been used experimentally for treating liver disease. The major advantage with using these cells is that the risk of rejection is very low. In trials spanning 2005 to 2010, autologous bone marrow cells were used as sources of cell therapy for a variety of liver diseases. Most of the clinical trials were small, from one to 40 patients and some showed a measure of improvement in liver function. As the field moves forward, researchers are trying to understand the details of how bone marrow stem cells contribute to liver regeneration, and whether transplanting particular populations of bone marrow stem cells could work better than whole bone marrow transplants.

Another approach being tested is to use a growth factor called G-CSF to stimulate blood stem cells in the bone marrow to leave the bone marrow and enter the blood. The circulating stem cells can be easily collected, separated from the other blood cells, and delivered back into the same patients as autologous transplants. Small clinical trials have tested this strategy in patients with end-stage liver disease as a result of alcohol or hepatitis B virus-induced cirrhosis. The procedure has been proven safe and in some cases beneficial effects have been observed for as long as 12 months. G-CSF can also be administered alone with the intention of stimulating the liver’s own resident stem cells to repair damage, and clinical trials are underway to evaluate this strategy.

Current research using mesenchymal stem cells

Mesenchymal stem cells are among the most ‘multipotent’ stem cells that remain in our bodies after birth. This means that they are still able to make a variety of different cell types. These stem cells are found throughout the adult body in tissue such as bone, muscle, cartilage and fat, and in the developing human in bone marrow, cord blood, placenta, fetal liver tissue and teeth. Researchers are keenly investigating whether mesenchymal stem cells can differentiate into hepatocytes in the body or be coaxed into making hepatocytes in the laboratory for transplantation. Preliminary trials have shown that patients with liver cirrhosis have benefitted from receiving a transplant of their own mesenchymal stem cells harvested from bone marrow, but larger, controlled trials will be necessary to predict whether this direction is worth pursuing and how exactly mesenchymal stem cells are exerting their effects.

Current research using pluripotent stem cells

In nature, the master stem cell is the embryonic stem cell because it can make an entire human being. But researchers have found a way to turn back the clock on adult cells and reprogram them to act like embryonic stem cells. These man-made stem cells are called induced pluripotent stem cells (‘pluripotent’ from the Latin words ‘very many’ and ‘having power’) and they can be made from skin or other tissue cells.

Canadian scientists have devised methods for turning human embryonic stem cells and induced pluripotent stem cells into experimental hepatocytes that closely resemble normal cells in the liver. In the short term, these cells are being used to predict how people will respond to various drug therapies. This is very important because drug metabolism by the liver varies considerably from person to person, and about 50% of drugs are taken off the market because of toxicity to the liver.

Currently, hepatocytes left over from transplants or hepatocyte cell lines derived from liver cancers are used as test sources for drug studies but variation and functionality can confound the results. So, having a ready supply of experimental hepatocytes could be a tremendous boon, and pluripotent stem cells could theoretically generate limitless numbers of such cells. Induced pluripotent stem cells offer the additional benefit of being able to provide patient-specific hepatocytes, which could be used to verify that a drug therapy would not harm a patient’s liver, as rejection-free hepatocyte transplants, and as a source for seeding artificial livers with patient-specific cells.

Further reading on liver failure

Readers may wish to peruse the recommended sites and below for more information about liver failure and the possible future applications of stem cells to treat this disease.

Canadian Liver Foundation
Health Canada
American Liver Foundation

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