George V. Mazariegos, MD
Director, Pediatric Transplantation
Children’s Hospital of Pittsburgh of UPMC
Since the first successful liver transplantation was performed in a child almost 40 years ago, this option has increasingly become a life-saving therapy for children with liver diseases such as biliary atresia. Interestingly, the next most common indication for liver transplant in children has been metabolic diseases such as tyrosinemia or urea cycle defects. Despite the availability of medical therapy for some of these diseases, the unpredictable nature of the disease and the potential long-term complications of tumors or neurologic problems has led to the use of liver transplant in these children. Results for liver transplantation have increasingly improved with experienced centers demonstrating high rates of survival exceeding 90 percent at one to two years. Of note, this includes caring for children who present in very sick condition with acute liver failure or for children with other conditions such as liver tumors.
At Children’s Hospital of Pittsburgh we have been very focused not only on successful survival outcome but also on assuring that children who undergo transplantation are achieving a highly improved quality of life. One of the ways that this has been achieved has been by developing new ways of handling immunosuppression, i.e., the medicines that are used to prevent rejection of the transplanted organ.
For example, by eliminating the routine steroids used in transplantation, we have seen a reduction with their associated side effects, such as growth delay or infections. At the same time, by modifying immunosuppression, our hope is to achieve a higher rate of children that are able to be on very minimal post-transplant immunosuppression or potentially be completely off immunosuppression altogether in the future. These developments led to collaboration with the Clinic for Special Children under the direction of Holmes Morten, MD, and Kevin Strauss, MD, who, in conjunction with our transplant team, have developed a protocol for consideration of liver transplantation in children presenting with classic Maple Syrup Urine Disease (MSUD). Our aim was to provide a comprehensive plan for assessing children and adults with MSUD and offering transplantation to appropriate patients in the safest way possible.
Treating Maple Syrup Urine Disease with Transplantation
As many of you are aware, liver transplantation was reported in a patient with Maple Syrup Urine Disease (MSUD) who had developed acute liver failure due to another cause in 1997; when this child received a liver transplant to correct her acute liver failure, her previously diagnosed Maple Syrup Urine DMSUD was metabolically cured.
Since the inception of the MSUD transplant protocol here last May, we have transplanted an additional 10 children with classic MSUD. These children ranged in age from 1.9 to 20.5 years and are now approximately an average of 10 months after transplant (range of 1.3 to 15 months). All the children have normal liver function and are currently enjoying an unrestricted diet. Amino acid profiles have normalized within a few hours after transplant and have remained so despite advancing to a regular diet of unrestricted protein. The initial patient transplanted is now stable over 5 years of follow-up; the more recently transplanted patients have also demonstrated normal liver function with normal plasma amino acid profiles.
Immunosuppression, as we noted earlier, remains one of the long-term concerns that post-transplant patients encounter. As opposed to earlier protocols that featured multiple drug regimens, our current immunosuppression relies on single drug therapy with steroid use only if there are episodes of rejection. Currently, approximately 40 percent of patients may encounter an easily treated acute rejection episode after liver transplant. Four out of 10 of our recently transplanted Maple Syrup Urine Disease (MSUD) patients experienced a mild episode of rejection that did require a brief course of steroids. All of the children are on a single drug (Tacrolimus) to control rejection.
What Are the Risks of Transplant Treatment for Maple Syrup Urine Disease?
Infections have historically been an important risk factor for transplantation, but we are seeing an improved infection rate following transplantation. For example, virus infections such as those related to CMV and EBV (cytomegalovirus and Epstein Barr Viral, respectively) have steadily decreased to less than 4 percent in our experience. A more feared complication, post-transplant lymphoproliferative disorder (PTLD) has similarly decreased to less than 3 percent. In our MSUD patients, no patient has developed CMV disease or PTLD.
Significant neurological recovery has been noted in the long-term patient who underwent transplant and subtle but clear improvements have been reported in several of the recently transplanted patients. These findings are now being objectively quantified by neuro-developmental testing done pre and post-transplant in subsequent transplant recipients.
Liver transplantation may also prove be a cost effective therapy for Maple Syrup Urine Disease (MSUD) that may reduce the long-term cost associated with medical care and treatment for acute metabolic decompensation. Most importantly, the uncertain risk of a devastating neurologic complication can be prevented with a successful liver transplantation. Although these children continue to have MSUD genetically, the transplanted liver supplies sufficient enzyme activity to metabolize unrestricted protein diets and maintain branch chain amino acid homeostasis.
These early results are encouraging and support the role of transplant as a treatment options for children and even adults with MSUD. We encourage review and discussion with families and their physicians regarding transplant as a therapeutic option.
Contact Us
Our transplant team is available for any questions regarding transplantation for MSUD at Children’s Hospital of Pittsburgh of UPMC 412-692-6110 or by e-mail at george.mazariegos@chp.edu. You may also reach our transplant coordinator, Kimberly Haberman, by phone or e-mail: kimberly.haberman@chp.edu.
We hope that with the addition of liver transplantation as a therapeutic option, the quality of life and outcome for children with Maple Syrup Urine Disease will be greatly improved.
Learn more about Children's Hospital's new immunosuppression protocols.
