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Robert Squires, M.D., Professor of Pediatrics, University of Pittsburgh
Clinical Director, Gastroenterology/Hepatology, Children's Hospital of Pittsburgh

Having maple syrup disease (MSD) requires a daily dietary vigilance to maintain proper metabolic control of this genetic condition. Strict adherence to the carefully planned diet will maximize a child's potential with this condition. However, such restrictions can be a challenge for the growing child and adolescent who becomes naturally curious to try new foods and new tastes. There are no food holidays or special occasions. The diet must be followed without exceptions. While it can be a tough diet to adhere to, it is doable.

Despite best efforts to strictly follow the diet requirements, a viral infection or vomiting spell can quickly result in poor metabolic control and precipitate a metabolic crisis. Early recognition and intervention during these "sick days" can prevent the more serious and devastating spells that result in brain swelling, coma and even death. Unfortunately, MSD does not always play fair. A patient can carefully and dutifully follow "the rules" of the diet and still develop a crisis. It is precisely this unpredictability that has prompted many patients, families, and health professionals to seek a more permanent solution.

As this is a genetic condition, it naturally follows that gene therapy could potentially cure the disease. This hope cannot be abandoned. However, gene therapy has not moved forward as quickly as many had hoped. Finding and developing the critical genetic material, safely incorporating it into the genetic material of the patient, and ensuring the material will produce a functional enzyme that will replace the defective one are just a few of the mountains on the horizon.

The defective enzyme in MSD is not located exclusively in the liver. In fact, other organs such as the brain, intestine, muscle and heart have high levels of the enzyme. Therefore, the idea that a liver transplant could provide a cure for an enzyme deficiency that is present in many body tissues seemed far-fetched. However, in the early 1990's a young French girl, diagnosed with MSD in infancy and with a history of metabolic crises, contracted the hepatitis A virus. This young lady was one of the unfortunate few who developed rapid liver failure from the hepatitis A viral infection and received an emergent liver transplant for that reason. Surprisingly, after the liver transplant, the child was able to eat a regular, unrestricted diet without developing a metabolic crisis. She underwent more sophisticated testing a few years after the transplant and her doctors found that while her isoleucine levels were very mildly elevated, her body could process large amounts of branch chain amino acids as quickly and efficiently as patients without MSD. It is following this experience, as well as and that gained from a MSD patient who received a liver transplant as a result of vitamin A toxicity, that has prompted a closer look into the possibility that liver transplant could serve as a potential metabolic cure for the disease.

Over the last 20 years of experience with liver transplant in children, patient survival and the complications associated with medications to prevent rejection have improved drastically. As the outcomes following liver transplant have improved, and the outcomes for dietary management of MSD are not without consequences, some families are beginning to consider liver transplant as a treatment option for their child.

The decision by the patient, family and health care provider to choose continued dietary management or liver transplantation is not easy. On the one hand, MSD is controlled by diet, the metabolic defect is not isolated to the liver and there are risks associated with liver transplant. On the other hand, dietary management is not all that easy, specific gene therapy is not on the horizon, there is genuine anxiety about the sudden development of a metabolic crisis, the cost for medical management is between $7,000-9,000 per year for well children and $100,000-500,000 for severe metabolic crises, and many issues surrounding liver transplant have been improved. (See Drs. Morton/Strauss' article for an estimate of medical treatment costs.)

At the University of Pittsburgh and the Children's Hospital of Pittsburgh, we gathered a number of critical personnel to develop a program to provide liver transplantation as an option for children with MSD. Those personnel included transplant surgeons, pediatric specialists in areas of metabolic disease, liver disease, and intensive care, pharmacist, dietitian, nurse practitioners, nursing staff with expertise in patient care and coordination, and the hospital administration. Our goal was to identify the best candidates for transplant, identify the best liver graft for the patient, and minimize the metabolic stress that would be associated with preparation for surgery. In addition, we needed to potential problems and have a strategy, which included TPN if necessary, to intervene should an altered metabolic state develop.

A strict decision "tree" was put into place once a MSD child was placed on the transplant list. First, only a healthy, whole, blood-type and size matched donor liver would be considered. Once a proper graft was identified and matched to a MSD patient, the family is notified. If the child has been clinically well and has not required a special or "sick day" formula within the last 3 weeks, the initial preparations for liver transplant were initiated. Once the child arrives in the hospital, their metabolic stability is assessed and a glucose infusion is started to minimize the metabolic stress. There is always the possibility that even if a patient is "called in", circumstances could arise that would result in the cancellation of the transplant. It is critical that all the proper pieces of the transplant puzzle be in place, and if they are not, then it is safer to cancel the operation and wait for the next time.

In the end, the decision to proceed with a liver transplant for a child with MSD comes down to an imperfect, but an increasingly better understood, effort to balance the various probabilities associated with proceeding with a transplant or not. The decision to continue with medical management is, on the one hand, comfortable, familiar, and avoids trading one disease (MSD) for another (suppressed immune system following liver transplant). On the other hand, dietary therapy is restrictive, expensive, associated with a number of quality of life issues, and does not guarantee freedom from the broad range of neurologic and metabolic crises. The decision to proceed to liver transplant is, on the one hand, free of dietary restrictions, and is associated with newer immunosuppression regimens that do not include steroids that allow some patients to eventually reduce medications significantly or come off of them entirely. On the other hand, it is also expensive, associated with real, albeit rare, risks of the operation, and requires daily medication which, for most, will be life long.

There is no "right" or "wrong" decision. The family, along with consultation from health care providers, will make the right choice for their child and family. At the same time, there will be some angst associated with the decision process, but this will allow one to become more familiar with themselves, their child's condition, and what the future might hold for their child; and this is a good thing.

Robert Squires, M.D.
Professor of Pediatrics
University of Pittsburgh
Clinical Director, Gastroenterology/Hepatology
Children's Hospital of Pittsburgh

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