Liver Transplantation for Maple Syrup Urine Disease
George V. Mazariegos, MD
Director, Pediatric Transplantation
Children’s Hospital of Pittsburgh
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 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% 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 and Robert Squires, MD, Clinical Director
of Gastroenterology and Hepatology at Children’s Hospital of Pittsburgh,
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. As many of
you are aware, liver transplantation was reported in a patient with 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 MSUD 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% of patients may encounter an easily treated rejection episode
after liver transplant. Four out of 10 of our recently transplanted 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.
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% in our experience.
A more feared complication, post-transplant lymphoproliferative disorder (PTLD)
has similarly decreased to less than 3%. 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 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.
Our transplant team is available for any questions regarding transplantation
for MSUD at Children’s Hospital of Pittsburgh (412) 692-6110 or by e-mail
at George.Mazariegos@chp.edu. You may also reach our transplant coordinator,
Lynn Seward, by phone or e-mail: Lynn.Seward@chp.edu.
We hope that with the addition of liver transplantation as a therapeutic option,
the quality of life and outcome for children with MSUD will be greatly improved.
