The liver is the largest solid organ in the human body and is essential for life.  As blood circulates through the liver, it performs a number of functions that are critical to sustaining life. These include metabolizing nutrients transported from the intestines, removing waste products from our body, filtering toxic substances and drugs from our blood, helping to maintain levels of blood sugar, fat, and hormones in our circulatory system, as well as participating in our immune defense against infection.

About 60 per cent of the liver is made up of liver cells called hepatocytes, which metabolize nutrients and detoxify the blood by removing harmful substances. A hepatocyte has an average lifespan of 150 days. This means that the liver is constantly renewing itself under normal conditions, much like our blood and our bones do.  Other cells within the liver include bile duct cells that transport bile necessary for absorption of fat and minerals as well as toxic products that are eliminated in the intestine. The third major cell population is macrophages and endothelial cells (reticuloendothelial cells) that contribute to the host immune system.

The liver is a very hardy organ that can withstand a great deal of abuse. Liver failure means that there is irreversible damage to the structure and function of the liver such that its effectiveness in maintaining so many of the body's essential functions is diminished beyond repair.  Individuals who develop liver failure can die with no warning within months of diagnosis.

Liver failure is increasing dramatically. Currently, the most common cause of liver failure is viral hepatitis - estimates are that the incidence of hepatitis C virus infection (HCV) will continue to rise over the next 10-20 years. However, a "lifestyle of excess" that is characterized by obesity and high triglycerides stresses the liver, such that the condition known as fatty liver is now emerging as a common cause of liver failure. Furthermore, deaths from alcoholic liver disease have doubled in the last 10 years in Britain, related to the eight-fold increase in young people diagnosed with alcoholic liver disease due to binge drinking.

Much like skin, blood and bone, the liver is designed to regenerate itself as a response to regular wear-and-tear and injury. Liver failure occurs when this process is inhibited or overwhelmed and shuts down. This can be the result of both an acute trauma to the liver or the evolution of chronic liver failure over time.

There are many different kinds of liver disease - what they have in common is that they affect the structure and function of the liver. Liver disease can be caused by viruses, drugs, alcohol, genetic defects and exposure to toxic chemicals. Some common symptoms and signs associated with liver disease include nausea, vomiting, reduced appetite, jaundice, low-grade fever, abdominal pain and fatigue.

Liver disease is often diagnosed by investigating liver enzymes , levels of bilirubin or disturbances in blood clotting. Liver failure can be a complication of other diseases including diabetes mellitus, heart failure and kidney failure and alcoholism. End-stage liver disease (ESLD) indicates that it is only a matter of time before the liver fails.

Some Common Causes of Liver Disease

Alcohol abuse is the leading cause of liver disease in the world. Over a period of time alcohol abuse can induce permanent changes in the liver, sometimes leading to cirrhosis of the liver, which is characterized by scar tissue or fibrosis and inflammation in a significant portion of the liver. While this damage is permanent, the liver is a large organ, and other portions may remain unaffected. However, as the disease progresses, more and more of the liver becomes scarred, the capacity for regeneration in the healthy portion diminishes, and liver failure results.

Hepatitis

Hepatitis is inflammation of the liver, most commonly caused viral infection or  ingestion of toxic drugs. Hepatitis A is a virus found in contaminated food or water that infects the liver. The liver usually recovers but occasionally hepatitis A virus infection is fatal. Hepatitis B is a virus transmitted through blood and bodily fluids from mother to baby, by sexual contact and drug use. Today the incidence of new cases of HBV disease is falling due to successful vaccination programs worldwide.

Hepatitis C is a serious and incurable liver disease that is becoming more common. Caused by the HCV virus that is most often transmitted by blood, HCV infection leads to chronic inflammation of the liver and cirrhosis. It is transmitted to others, often through blood or drug use (needle-sharing). It can develop without symptoms and progress to a chronic stage before someone even knows they are a carrier.

Heavy metals, such as lead or copper, and chemicals found in pollution, fabrics, home insulation, pesticides, to name just a few sources, may also affect the liver and lead to liver failure over time.

While the liver can tolerate and recover from a certain amount of abuse, there are often no warning signs that it is failing until it is too late. Once the line is crossed from chronic liver disease to end-stage liver disease or liver failure, the options become stark. There is no "liver dialysis" that can rehabilitate liver function in the way that kidney failure is treated.

Liver transplantation is currently the only effective treatment for liver failure, but it has many drawbacks, including a shortage of donors, risk of rejection, and risks associated with surgery. Many people die with chronic liver failure waiting for a donor organ. It is estimated that for every donor organ there are 10 patients on the waiting list.

In 2004, doctors at Hammersmith Hospital in London successfully treated chronic liver failure in a small number of patients using autologous transplantation with bone marrow stem cells (BMSCs). This is a technique developed for the treatment of leukemia. Blood is taken from the patient and separated into its components. Then, stem cells are taken from the white cells, cultured and injected into the hepatic artery in the liver where they begin the task of rebuilding the liver. The advantage of this procedure is it uses the patients' own cells.

Bone marrow is one of the sources of mesenchymal stem cells (MSCs), which are found in bone, muscle, cartilage and fibrous tissue. These are among the most multipotent stem cells that remain in our bodies after birth. This means they have the potential to become a variety of different cells, depending on what is needed.

For example, a Japanese team is investigating MSCs derived from the dental papilla of discarded wisdom teeth which might someday be used as a source of MSCs for stem cell therapy. Other sources for MSCs include cord blood, placental tissue and fetal liver tissue, which contain stem cells that are multi-potent and proliferate easily. In addition, adult stem cells are more pliable than we first believed if they are removed from their niche and put to work in other organs. In the case of liver disease, this means an MSC might be coaxed to generate hepatocytes.

With adult stem cells now discovered in most of the body's organs, one might assume that the regenerative capacity of the liver is due to liver stem cells.  However, it has not been easy to isolate these cells. Because normal hepatocytes have an intrinsic capacity to replace themselves, many investigators believe that this is sufficient to explain how the liver repairs itself. However, there does seem to be a small section of the liver where hepatic progenitor cells actively give rise to new liver cells. Research in other organs suggests that a certain signal can mobilize stem cells from the bone marrow into the circulatory system. The theory is that as the blood circulates through the liver, these cells home into the area that needs repair.

Whatever the sources, researchers in the field of regenerative medicine need to understand the mechanism by which these new cells engraft onto the liver. Early indications are that cells cultured from MSCs and injected into the patient take on all the liver functions. This is promising evidence that scientists someday may be  able to repair the failing liver, either endogenously (by stimulating the stem cells that normally reside in the body) or exogenously (by cell transplantation). Some scientists even believe that we are not far from being able to re-grow portions of the liver in culture for partial organ transplantation.

However, liver failure is not only due to the lack of healthy cells. While most biotechnology and research laboratories are refining the methods they use to proliferate and differentiate cells in sufficient quantities so they can be used therapeutically, other teams are examining the process of fibrosis that distorts the shape and function of the liver. It appears that MSCs may play a role in inhibiting this destructive process. In any case, while new liver cells derived from stem cells might temporarily support impaired liver function, it is unlikely that they could restore the original liver structure and reverse scarring and this may be a major impediment to the treatment of patients with chronic liver disease.

For this reason, current therapeutic applications are concentrating on "bridge therapy", meaning cell therapy to give the liver a reprieve from progressive failure so that it might recover spontaneously or to buy time until a donor organ becomes available. Researchers envision the day when a patient could be hooked up to an artificial liver, which would take over all the functions usually carried out by their own liver, as is currently done in kidney dialysis.  Because of the liver's ability to quickly regenerate itself, with several dialysis sessions a day over a period of months they believe the patient's own liver would have enough resting time to regenerate and repair any damage.

Our thanks go to the Stem Cell Network in Canada for their work on this information