Liver damage reversal

“A drug that reverses severe liver damage could be used to treat disease in heavy drinkers”, reported The Guardian on December 27 2007. BBC news said that researchers have claimed that scarring on the liver caused by heavy drinking and hepatitis could be “halted or even reversed” by blocking “a vital protein which helps it to form”.

The research behind these stories is a laboratory study conducted primarily in mice with a chemically induced fibrotic liver disease. It should be noted that within the research article, the researchers imply that it is unknown whether their findings apply to other types of liver disease (such as alcoholic liver disease as mentioned in the news reports) and that further research is needed.

A treatment for alcoholic cirrhosis in humans based on this technology is still a long way off and for now, prevention is better than a potential cure. The NHS Choices Live well section has extensive information and practical advice on alcohol consumption.

Where did the story come from?

Drs Martina Buck and Mario Chojkier from the University of San Diego and the Veterans Affairs Healthcare Centre in California carried out the research. The study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Cancer Institutes (NCI), and the Department of Veterans Affairs.

The study was published in the online peer-reviewed medical journal: PLoS ONE.

What kind of scientific study was this?

It is thought that a particular chemical pathway, the RSK-C/EBP β phosphorylation pathway (a sequence of chemical reactions leading from one compound to another), is involved in liver healing (in response to liver damage) and leads to the formation of scar tissue in the liver. This scar tissue is ultimately the cause of liver cirrhosis and fibrosis. The researchers were interested in seeing what happened if the RSK pathway was blocked.

In this laboratory study, the researchers induced a liver disease in mutant and normal mice that they said was “comparable to established severe liver fibrosis in humans”. The disease was induced by injecting a liver damaging chemical - carbon tetrachloride (CCI4) - into the mice over 12 or 16 weeks.

The mutant mice had an altered gene (C/EBP β) inserted into their DNA which blocked the RSK chemical pathway.

The researchers then removed the livers from both groups of mice and assessed the severity of the disease by looking at their cells under a microscope and by examining the concentration of specific chemicals that act as markers of disease.

The researchers also used human liver cells grown in the laboratory to explore how interrupting the RSK chemical pathway might affect the progression of disease, and confirmed these findings by further experiments in live mice.

The researchers also looked at what happened if the RSK chemical pathway was inhibited in mice that already had liver disease. A fibrotic liver disease was induced in mice by injecting them with the liver damaging chemical for eight weeks. For a further four to eight weeks, some of the mice were then also injected with a peptide (a very short protein) that blocks the RSK chemical pathway. The researchers then compared the mice that had been injected with the peptide with those that had not.

Finally, the researchers looked at liver tissue taken from four people with severe liver fibrosis caused by infection with hepatitis C, and from three people without liver disease. They looked at whether the RSK chemical pathway was active in either of these groups by examining cellular proteins.

What were the results of the study?

The researchers found that less severe liver fibrosis developed in mutant mice where the chemical pathway was not working than in the normal mice. This was evident because less damage was seen on microscopic assessment of the liver; there were lower levels of collagen (a component of scar tissue) and other chemical indicators of fibrotic disease; and reduced inflammation.

The researchers also found that interrupting the RSK chemical pathway in normal mice reversed some of the liver damage and prevented further damage on exposure to the liver damaging chemical.

By looking at human and mouse liver cells in the laboratory, the researchers were able to confirm that in cells in which the RSK pathway was interrupted there was a greater activation of the pathway that led to the killing off the cells that produce scar tissue.

Finally, they found that the RSK chemical pathway was more active in the livers of the people with severe liver disease than in those without.

What interpretations did the researchers draw from these results?

The researchers conclude that their study has shed further light on how the RSK-C/EBP β phosphorylation pathway is involved in response to liver cell injury and how it ultimately leads to liver fibrosis.

They stress that their findings are limited to the “liver injury and fibrosis model” induced by the liver damaging chemical, carbon tetrachloride (CCI4) in mice. They conclude that more research is needed to see whether the findings apply to other types of liver disease including “alcoholic liver disease”.

What does the NHS Knowledge Service make of this study?

This complex laboratory study used recognised methods to explore the roles of different proteins at the cellular and organism level.

However, this study’s findings do not necessarily apply to all liver diseases. Alcohol misuse can lead to different types of alcoholic liver diseases including cirrhosis, fatty liver or hepatitis. The authors themselves say that this study uses a particular model of liver injury and fibrosis and that “it is important to [establish whether the findings are relevant] in other animal models that reflect other causes of human liver fibrosis, such as biliary cirrhosis, alcoholic liver disease, immune liver injury and genetic iron overload”.

This is mainly a study in mice and the findings will not necessarily apply directly to human beings. The study did not test the effects of inhibiting the RSK pathway on human beings. The technology that could reverse liver fibrosis and cirrhosis in humans is at present only a distant prospect.

For now and for the near future, prevention of liver disease is better than a potential cure. However, the findings are of great interest to the scientific community and shed some light on the complex processes that occur in cells in certain types of liver disease.

Sir Muir Gray adds…

Don’t even think this is a reason to hit the bottle.