Since liver diseases in adults and children are on the rise, early diagnosis and prevention play a major role in management. Research in liver diseases is the key to the future. Given the volume of clinical cases in our country, we have the potential to do significant clinical and laboratory research but unfortunately the lack of funds prevent us from doing so. Our foundation is best poised to do meaningful research since we operate out of one of the largest centres for liver and pancreatic diseases in the country. With sufficient funds we will be able to achieve breakthroughs that will help us manage patients better.
Liver regeneration +
Human liver has a remarkable capacity to regenerate at an astonishing pace and grow to a larger size after part of it is removed. It is the only major human organ that can do so. By about 2 weeks after removal of part of the liver, most of the regenerative response is complete. The mechanisms involved in this are very complex and have not been completely understood. Understanding these mechanisms of liver regeneration is likely to have a major impact on the management of certain liver diseases and living donor liver transplantation.
Let us consider the situation of living donor liver transplantation as an example of why research on liver regeneration is important. If a son is donating to his father or mother, the donor undergoes removal of the right lobe of liver commonly. This procedure will remove about 60% of the donor’s liver mass (the idea is to get a liver that is at least 0.8% of body weight of the recipient). If the liver transplant with a lesser amount of liver, the new liver gets injured by its own blood flow (called portal hyperperfusion), fails to function well and is less likely to regenerate. This ultimately results in either a loss of the new liver or death of the liver transplant recipient.
It is interesting to note that live liver donors can recover completely with only 40% remnant liver volume after their operation, whereas liver recipients (who have pre-existing liver disease) need a larger volume of liver to survive the operation. Understanding liver regeneration by high quality research is likely to result in understanding why a larger size of liver is required by the liver transplant recipient, and the mechanisms behind injury to the new liver if a smaller sized liver is used for transplantation. Though there is some understanding on why these could be happening, the information available is incomplete and does not have wide clinical application. Further research in this area may allow transplantation of small sized livers successfully into patients undergoing living donor liver transplantation resulting in increased donor safety, as liver donors can donate smaller portions of their liver (say, their left lobe or part of left lobe) and would not run the risk of postoperative liver failure.
Another liver disease that would be benefited greatly by research on liver regeneration is acute liver failure. Here, there is sudden massive loss of liver cells due to an acute insult. Common causes for acute liver failure include viral hepatitis and paracetamol poisoning. Even though most of the functioning liver cells die in acute liver failure; the basic architecture (framework) of the liver is well preserved in this situation (unlike chronic liver disease where the framework is lost completely). Liver transplantation is life saving in acute liver failure as it immediately provides a functioning mass of liver cells. If the mechanisms of liver regeneration are better understood, we may be able to induce proliferation of the remaining undamaged liver cells in patients with acute liver failure quickly. If this is achieved, it may be possible to avoid liver transplantation in the management of acute liver failure.
Immunosupression ( liver repopulation)+
The Achilles heel in long term care of any patient who undergoes transplantation is immunosuppression. The immune system of the person who receives organ transplantation (recipient) will perceive the new organ as foreign (as belonging to somebody else) and try to destroy it by a process called “rejection”, wherein the recipient’s white blood cells and/or antibodies cause direct damage to the transplanted organ. In order to prevent rejection, transplant recipients are given medications that blunt the body’s immune response. These medications are called immunosuppressants. Immunosuppressants are non specific and lead to a generalized decrease in the body’s immune response. Apart from preventing rejection of the new organ, these medications predispose the transplant recipient to infections and tumors. Some of the immunosuppressant medications can also lead to kidney damage (sometimes requiring kidney transplantation) and diabetes mellitus.
Current attempts worldwide are towards minimizing immunosuppression or developing new medications that have a higher safety profile. However, the holy grail of transplantation would be the ability to perform organ transplantation without any kind of immunosuppression. At NFLR, we intend to promote research into exploring the possibility of performing transplantation without immunosuppression.
Transplantation for metabolic liver diseases+
Metabolic liver diseases refer to a heterogenous group of diseases that are due to genetic abnormalities, usually affecting a single gene, which result in the inability of the liver to synthesize a particular gene product. The gene product is usually a protein which performs a unique, vital function either in the liver itself or in other organs. The liver itself may or may not be affected by the disease. Typical examples of metabolic liver disease are Criggler-Najjar syndrome, primary hyperoxaluria, urea cycle disorders, tyrosinemia, haemochromatosis and Wilson’s disease. Some of them, like Wilson’s disease, tyrosinemia and haemochromatosis, affect the liver and present as liver failure. The liver itself is normal in a few other metabolic diseases like Criggler-Najjar syndrome and urea cycle disorders. In these latter diseases, the problem is caused by a lack of the protein product which affects some other body function or organ other than the liver.
Most of these diseases are currently being treated by orthotopic liver transplantation, where the defective native liver is completely removed and a new liver from a donor without the genetic defect is transplanted into the recipient. Though the metabolic liver disease is cured by the orthotopic liver transplantation, patients will have to be on lifelong immunosuppression. This is required as the new liver is foreign to the patient and without immunosuppression, the patient’s body will destroy the new liver by a process called “rejection”. Problems with immunosuppression are susceptibility to infections, tumours and the possibility of irreversible kidney injury.
Auxiliary liver transplantation is a type of liver transplantation in which only a part of the genetically defective liver is removed. The healthy donor liver is implanted into the recipient in the space thus created. After this type of transplantation, both the genetically defective but otherwise well functioning liver and the new liver, which doesn’t have the genetic defect, exist simultaneously in the patient. Immunosuppressive drugs have to be given here as well but the advantage here is that when gene therapy becomes available for these diseases in future, we may gradually withdraw the immunosuppressive drugs for the patient. Gene therapy would have cured the underlying liver disease and withdrawal of the immunosuppression would result in the gradual rejection of the transplanted liver, which will eventually disappear. It is possible to avoiding lifelong immunosuppression when auxiliary liver transplantation is done.
Only a few centres in the world do “Auxiliary liver transplantation”. Prof. Mohamed Rela has one of the largest personal experiences in performing auxiliary liver transplantation and has performed the first auxiliary liver transplantation in India. Performing auxiliary liver transplantation successfully in metabolic liver diseases gives a huge research opportunity, especially when gene therapy becomes available.
BA is a progressive cholangiodestructive disease of the intra and extrahepatic bile ducts leading to cirrhosis and end stage liver disease. Its incidence is 1 in 18,000 live births. It is the most common cause of cholestatic liver disease in children. It is also the major cause of liver transplantation in children. 50 percent of all liver transplantation is for Biliary Atresia. The etiopathogenesis of Biliary Atresia (BA) is multifactorial and no single cause has been identified thus far but the final causal pathway involves cholestatic injury resulting in ductular destruction and proliferation. BA is fatal within 2 years of life if left untreated. Treatment involves a sequential strategy combining Kasai Portoenterostomy (KP) as first-line and Liver transplant as second-line treatment if Kasai fails to establish bile flow and/or progressive liver fibrosis and cirrhosis occurs.
Our research studies concentrate on the etiopathogenesis of BA, causes for the progression to end stage disease and the effectiveness of KASAI portoenterostomy. We will be looking into these at molecular and cellular levels using histopathological studies and ancillary studies such as immunohistochemistry and immunofluorescence. We are currently collaborating for these research studies with Dr. Pranav Shivakumar from Cincinnati Children’s Hospital Medical Centre, Ohio USA.
The National Foundation for Liver Research was established with the objectives of promoting scientific research in liver disease, improving public awareness about organ donation and expanding access to life saving liver surgery for patients irrespective of their economic background