Dr. Holmes Morton MD and Kevin A. Strauss MD
Clinic for Special Children
THE EFFECT OF LIVER TRANSPLANTS ON MAPLE SYRUP DISEASE:
In May 2005 Dr. George Mazariegos from the Children's Hospital of Pittsburgh Starzl Transplant Institute presented an abstract at the annual Pediatric Surgery and Transplant Meetings entitled, Liver Transplantation for Maple Syrup Urine Disease (MSD): Protocol and Preliminary Results. (Mazaregos G et al 2005) The perioperative management protocol for MSD and the liver transplants were the result of a two year collaboration between the Clinic for Special Children and Starzl Institute. The results of 6 cases were discussed by Dr. Mazariegos, including a MSD patient from the Clinic for Special Children who was transplanted 8 years ago at Childrens of Philadelphia, but now receives post-transplant care in Pittsburgh . The 6 patients were 2-8 years of age at the time of transplant with a whole cadaveric liver. In two cases, rejection was managed with Prograf and steroids, and, in four cases, with antithymocyte preconditioning followed by Prograf monotherapy. All patients recovered from the surgery. Allograft function remains normal in all patients. Metabolic cure was apparent in all cases as an immediate and sustained increase in dietary leucine tolerance from 15-20 mg/kg-day to an unrestricted protein diets. Leucine intakes greater than 150 mg/kg-day were tolerated by all six patients, and plasma amino acid profiles were stable during periods of fasting, after steroid use, and during catabolic illnesses provoked by intercurrent infectious. The molar ratios of the branched-chain amino acids concentrations in blood remained stable, which indicates rate of oxidation amino acids in liver was regulated to maintain constant plasma amino acid profiles. (FIG 1 & 2 see page 14) In our first MSD transplant patient the metabolic effects of the liver transplant have been stable for more than 8 years. In addition to biochemical stabilization, all patients to have shown unanticipated neurological benefits of stabilized plasma amino acid concentrations. Decreased hyperactive behavior, better attention span, improvements in gross motor and fine motor skills have been observed. Marked improvements in the neurological exam was especially apparent in our first transplant patient over the first two years after her transplant. Formal studies are in progress to document and explain these effects of liver transplants upon the brain. Since submission of the Abstract in December 2004, two more elective transplants for MSD patients have been done at Children's of Pittsburgh. Worldwide 15 liver transplants have been done as treatment for MSD. There was one perioperative death in a MSD patient referred for elective transplant. She had a living related donor transplant in Boston, and died soon after surgery because of acute graft rejection. The Clinic for Special Children and Childrens Hospital of Pittsburgh proposed our collaborative effort to develop a perioperative protocol and formally evaluate the benefits of elective cadaveric liver transplants for MSD, not only because of the remarkable success in our first our MSD transplant patient, but also in response to the death of the second patient.
THE CLINIC FOR SPECIAL CHILDREN PERSPECTIVE ON PROBLEMS RELATED TO LIFETIME MEDICAL TREATMENT OF MAPLE SYRUP DISEASE:
Over 16 years, we have cared for 46 newborns with Maple Syrup Disease (MSD). Whencompared to patients with MSD from 20-30 years ago, when death, long hospital stays, and chronic disabilities were commonplace, our group of young patients has done well. (Morton 2000, Strauss & Morton 2003) Before 1988, 14 of 36 (44%) Mennonite infants died before age 10 years from brain herniation. Since 1988, we have not had a death from cerebral edema in our patients, but, one of our 5 year old patients did suffer a stroke as a result of acute brain edema.
Our opinions about the problems and risks of long term medical treatment of MSD, versus risks and benefit of liver transplant, are influenced by the continued risk of brain injury and death from cerebral edema during the first 10 years of life, and by emerging problems related to the care of teenagers and adults with MSD. For either group of patients, risks and costs of medical management versus transplant should be assessed over intervals of 10 years or longer. Although we have reported significant improvements in the care of infants and children with MSD patients within Pennsylvania, elsewhere neonatal diagnosis and treatment are delayed, approapriate long term monitoring of therapy is not available, and access to care during intercurrent illnesses is limited. (Morton 2002a) When access to treatment is poor, then the risks and costs for younger MSD patients remains high. The care of older MSD patients is problematic everywhere. Within our prospectively treated group of 46 patients, 11 are now teenagers. We are also responsible for 18 adults with MSD, who came to the Clinic after diagnosis and treatment at other medical centers. In Pennsylvania, as elsewhere, medical services for patients with MSD who are over 18 years of age are essentially non-existent. No Internal Medicine practices in Pennsylvania offer outpatient specialty medical care for adults with MSD. No hospital in Pennsylvania has an experienced medical staff , MSD-TPN, and amino acid analysis to provide care for an adult with MSD and metabolic illness. A MSD counterpart to maternal PKU doesn't exist. All support for treatment of MSD through the Pennsylvania Newborn Screening Follow-up Program ends when patients reach age 21. The lack of medical services for adults with MSD is the major risk factor when estimating the cumulative risks of disability or death from MSD over a 10 year span of adult life. In addition to the lack of medical services for the adults with MSD, it is increasingly apparent that adults with MSD have different problems than infants and young children. Adherence to strict dietary therapy is difficult for teenagers. As growth slows and muscle mass increases in the late teenage years, tolerance of dietary protein decreases and dietary control becomes more difficult, even with good compliance. Reversal of catabolic illnesses is no less difficult in adults than in younger patients. And, subtle, and not so subtle, neurological problems are being observed that arise from the cumulative effects of poor metabolic control, unbalanced uptake of amino acids into the brain, and, no doubt, trace nutrient deficiencies that arise from severely restricted diets and dependence upon formulas and other artificial foods.
LIVER TRANSPLANTS AS TREATMENT FOR GENETIC DISORDERS AND THE LOW POTENTIAL OF HEPATIC GENE THERAPY:
The collaborative liver transplant program for MSD at the Starzl Institute reflects a significant change in our thinking about therapeutic liver transplant. The majority of liver transplants, in Pittsburgh and elsewhere, are done because of liver failure. Our patient with MSD who first underwent transplant was referred because of vitamin A induced liver failure. Elective transplants are now being done for MSD, Crigler-Najjar disease, and urea cycle defects to protect the brain. In these, and many other genetic disorders, the liver is a central site of metabolic control for amino acids, bilirubin, ammonia, and other compounds that cause acute injury or chronic degeneration of the brain. As more is understood about the relationship between liver metabolism and brain growth, development, and function such indications for transplant will increase.
Our collaboration also reflects an opinion that the potential for cure of MSD by hepatic gene therapy within the next 10-20 years is extremely low. This is an issue we have thought about carefully.
Between 1990 and 2003, the Clinic avoided making referrals for liver transplants in patients with Crigler-Najjar disease (CN), which a severe form of hyperbilirubinemia for which liver transplant had been an accepted therapy. We developed treatments to prevent bilirubin injury of the brain in infants and children, then waited for an effective gene therapy to develop. In the early 1990s, many physicians and scientists felt that CN patients would be ideal candidates for "hepatic gene therapies." And, in 1990, most of us believed that a form of gene therapy would be available to these patients in 5 years or less, that is, before 1995. The Clinic sponsored two scientific meetings to review possible methods of hepatic gene therapy for Crigler-Najjar disease in 1999, and 2003. Dr. Morton also gave talks about the treatment of CN disease at two international meetings at Rockefeller University in New York in 1996, and at Erasmus University in the Netherlands in 2000. After these four meetings to discuss experimental gene therapies, we concluded by June 2003 that liver transplant was the only form of "hepatic gene therapy" that would be available to our patients with CN disease within the next 10-20 years. This conclusion reflected a perceived lack of progress in human gene therapy, and improvements in the outcomes of patient undergoing liver transplants. We now think delaying the liver transplants for patients with Crigler-Najjar disease with the rational that the many problems with human gene therapies would soon be solved, is not a justifiable. In the past year, 4 of our 24 CN patients have undergone elective liver transplants at Pittsburgh Childrens. Three of the patients have recovered from the transplant, one continues to have problems with rejection and side effects from immune supression. The most obvious reason to refer patients with CN and MSD for liver transplant, rather than wait for gene therapy, is that transplant is available as an established, curative therapy. No form of hepatic gene therapy is available. Liver transplants have been done for more than 20 years, Children's of Pittsburgh has done more than 4000 liver transplants in children. Over this time many complex problems related to surgery and graft tolerance have been solved. Outcomes have steadily improved. In contrast, the translation of the most promising forms of experimental hepatic gene therapy into the earliest "Phase 1" human studies, using patients with CN or MSD, has not begun. The first experimental studies of a new technique would not be a therapeutic trial, but would be studies to evaluate the safety of the proposed method of gene therapy. The highly publicized death of a young man in Philadelphia in 1999 made it very unlikely that Phase 1 Trials will ever be done again with patients who have unstable underlying metabolic disorders. He had a urea cycle disorder and died during the Phase 1 study of hepatic gene therapy using a virus to infect the liver and thereby, temporarily, introduce a new gene into a small number of liver cells. An immune response to the virus caused fever and catabolism, and, ultimately, the boy died of an inflammatory response to the virus that delivered the new gene, and the resulting biochemical intoxication from his metabolic disorder. Had these same studies been conducted with patient with Crigler-Najjar disease conducted with patient with Crigler-Najjar disease or MSD, the result would have been the same - metabolic intoxication, brain injury, and death, arising from the catabolic response to viras gene vector. For the foreseeable future, gene therapy trials that involve patients with unstable metabolic disorders will be considered unethical.
When, or if, a new method of hepatic gene therapy does complete the earliest non-therapeutic studies about safety, complex questions will remain to be answered about how well the new gene-enzyme complex controls blood and brain biochemistry after a high protein meal and during catabolic illnesses. Successful treatment of MSD by gene replacement, in particular, will require that a very high percentage of liver cells, probably more than 80%, acquire stable, highly regulated BCKAD enzymatic function. Current methods of hepatic gene therapy in animals introduce very low levels of gene/enzyme activity, typically into less than 1% of liver cells. For this reason, even if one of the current hepatic gene therapies could be safely done in humans, such low levels of enzyme expression would not be therapeutic for MSD. The lethal response to the viral vector in the urea cycle trial in Philadelphia suggests too that problems can be expected related to long term immune tolerance of the liver cells transformed by gene therapies. Controlling immune responses to viral gene vectors is likely to be no less problematic than the immune suppression now needed to allow tolerance of a transplanted liver. For these, and many other reasons, our opinion is that therapeutic trials in humans to prove that any form of hepatic gene therapy for MSD is as safe, as effective, and as enduring as whole liver transplants are extremely unlikely within the next 10-20 years. The choice facing parents and patients with MSD is between long term medical treatment and liver transplant.
WHY HAVE SOME PATIENTS WITH MAPLE SYRUP DISEASE UNDERGONE ELECTIVE LIVER TRANSPLANTS?
First, when MSD is poorly controlled by diet, and access to specialized care during metabolic crisis is not available, then the risk of progressive neurological disabilities, or death from cerebral edema, over a 10 year period is very high, and, in our opinion, exceeds the risks associated with liver transplant. This is true for children and adults. Second, liver transplant for MSD controls the biochemistry of MSD sufficiently to allow an unrestricted diet, and afford protection of the brain during intercurrent illnesses. (Morton et al. 2002b; Bodner-Leidecker et al. 2000; Wendel et al. 1999; Netter et al. 1994)
It is also of great interest to us, that cure of MSD through liver transplant has been associated with unexpected improvements in brain function. We attribute this to the stabilization of the plasma amino acid profile. (FIG 1&2) Many effects of MSD upon the brain can be understood in terms of the abnormal use of 8 essential amino acids that compete with leucine for entry into the brain. In infancy, the slow uptake of one or more essential amino acids by the brain results in poor growth and development of the brain. Clinical signs of the amino acid dysmetabolism in infancy include chronic irritability and anorexia, but, years later are manifest as mental retardation and cerebral palsy-like physical disabilities. Poor metabolic control in school age children is associated with hyperactivity, attention deficit disorder, impulsivity, and mood disorders . The same chronic biochemical disorders in teenagers and adults cause adult variants of attention deficit disorder, generalized anxiety disorder, panic attacks, mood and appetite disorders. Maternal MSD will become an increasingly important issue. Fetal exposure to poorlycontrolled maternal MSD will, as in PKU, place these infants at high risk for severe neurodevelopmental problems that begin in utero. Our experience suggests that middle age adults with poorly controlled MSD may have declining cognitive function, early onset parkinsonism, and mood disorders. We do not doubt that many of these problems can be prevented by better metabolic control, through improvements in formulas and metabolic foods combined with better medical treatment of MSD during intercurrent illnesses. However, under the best of circumstances, current medical treatment of MSD in the adult does not appear to benefit brain nutrition and function as much as liver transplant does. As the neurological effects of liver transplant are better understood and documented, this may emerge as an important indication for transplant, particularly in teenagers and adults.
COSTS OF LONG TERM MEDICAL TREATMENT OF MAPLE SYRUP DISEASE AND LIVER TRANSPLANT:
The costs of liver transplant are high - $200,000 is a figure often quoted, but the actual costs depend upon the method of payment and complications after transplant. As with MSD, the ultimate costs of liver transplant in an individual patient over a 10 year period are difficult to predict. At the Clinic for Special Children, the average cost of medical care for a patient with MSD is relatively low because we are a non-profit medical Clinic , and are heavily subsidized by the Mennonite and Amish Communities. We estimate $7,000-9,000 per patient per year, or about $80,000 per 10 years of follow-up. However, we have little control over in-hospital treatment of illnesses. Over a 16 year period, we have managed patients through more than 200 hospitalizations for acute illnesses. Approximately 1/10 of these admissions were prolonged and generated hospital bills in excess of $100,000. The cost of even routine hospital care for our patient has increased dramatically. The daily room rate at our hospital has increased from $350/day in 1989 to over $1700 per day. One of our patients was recently billed over $11,000 for a single day in hospital because of a respiratory tract infection. More than $9000 this bill was a hospital pharmacy charge for purchase and preparation of a medication called Synagis. At the Clinic the purchase and administration of the same medicine costs $900. Costs associated with management of a newborn with MSD who needed bowel surgery and heart surgery exceeded $500,000. Two life threatening cases of cerebral edema exceeded $500,000 each. The lifetime medical costs associated with neurological disabilities are extremely high. One 5 year old MSD child suffered injury from brain herniation that cause partial paralysis, speech impairment, and blindness, generated medical costs approaching $1 million dollars. Finally, it is especially difficult to estimate the long term costs of adults with MSD who, because of brain injury or chronic metabolic intoxication, cannot work or live independently.
Much of the debate regarding transplant for MSD centers on the "treatability" of this complex disorder over the lifetime of the patient. Based upon our experience at the Clinic for Special Children, physicians, parents, public health officials, and medical insurers have underestimate the long term risks of neurological problems that accrue even with the best medical and nutritional management. We now expect all of our patients with MSD to survive to adulthood. The cumulative costs for medical treatment of an individual with MSD over 10, 20 and 40 years will, in the majority of cases, exceed the cost of liver transplantation.
Liver transplant provides adequate control of Maple Syrup Disease to allow a normal diet, and prevents systemic metabolic intoxication and cerebral edema during catabolic illnesses. The stabilization of blood amino acid concentrations following transplant is associated with significant improvements in brain function. We do not recommend liver transplant for all patients with MSD. Risks and costs must be assessed on a case-by-case basis. For some patients, liver transplant is reasonable, cost effective treatment.
A FINAL COMMENT:
The use of organ transplants to treat genetic diseases is one way to translate the remarkable recent advances in the molecular biology and genetics into genetic medicine. As our understanding of genetic diseases increases, organ transplantation should become an increasingly important way to help patients who suffer from these difficult disorders. Being able to provide this help depends most obviously upon the innovative, difficult work of those in transplant centers, and upon organ donor programs. Yet, ultimately, the ability to provide such extraordinary help to an individual requires the sustained belief within our society that such care is a necessary and important part of health care.
Liver Transplant as treatment for Maple Syrup Disease: Our perspective as Pediatricians