Metabolic effects of liver transplantation in MSUD
BCKAD is expressed and metabolically active in liver, muscle, heart, brain and other tissues (19). The efficacy of orthotopic liver transplantation for MSUD indicates that introducing about 10% of normal BCKAD enzyme on a whole body basis is sufficient to maintain peripheral amino acid homeostasis in the face of unrestricted protein intake (Figure 2) (19). The transplanted enzyme is subject to regulation, allowing it to adapt oxidation rates to prevailing physiologic conditions and maintain molar constancy of the plasma AAP despite large nitrogen fluxes that accompany protein loading, fasting and infectious illness (Figures 1 and 3). While transplantation of a single kidney would introduce a similar whole-body fraction of BCKAD (9–12%), it may not afford the same degree of metabolic control. The anatomical position of the transplanted enzyme may be relevant to its physiological effect; the liver is normally a major site of regulatory oxidation of surplus amino acids that result from both dietary excess and muscle proteolysis (8,9,16,20). Figures 1, 3 and 4 show that liver transplantation not only eliminates high and variable BCAA levels, but also protects children from essential amino acid deficiencies, which may be of equal importance for optimizing physical and neurological development (4,21–26).
Figure 4. Plasma amino acid concentration ratios for patients 2–11 before (n = 112) and after (n = 94) liver transplantation (LT). The overall plasma amino acid profile normalizes following transplant, as shown here by stable concentration ratios among the BCAAs (valine:leucine), and between BCAAs and other essential amino acids (leucine:phenylalanine), neurotransmitter substrates (leucine:tyrosine), and nonessential amino acids leucine:alanine). Note: y-axes on log 2 scale.
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In previous work (2,4), we hypothesized that two major mechanisms account for the acute and chronic neurological manifestations of MSUD: (i) unbalanced transport of LAT1 substrates across the blood-brain barrier alters cerebral protein turnover and monoamine neurotransmitter metabolism (23,27–29) and (ii) intermittent and chronic elevations of BCKAs disturb cerebral transamination fluxes that normally maintain ‘fast’ neurotransmitter pools (Figure 2) (26,30–32). Based on the present experience, we expect that such ongoing neurochemical disturbances cause cognitive, motor and psychiatric morbidities, which can improve after surgery despite persistence of cerebral BCKAD deficiency in all transplanted patients (Figure 2).
Weighing risks, costs and benefits
At the Clinic for Special Children, the average annual cost of nutritional and medical care for a patient with MSUD was $7000–$9000 per patient per year (U.S. dollars, surveyed in 2002) or about $80,000 per 10 years of follow-up. Thus for most individuals with classical MSUD, the lifetime costs of nutritional management will greatly exceed those associated with transplantation. Importantly, cost averaging does not capture the extraordinary monetary and human costs experienced by individual patients. Acute metabolic decompensation with attendant cerebral crisis can strike at any age and culminate in neurological catastrophe (1,3–6). Before 1988, 14 of 36 (44%) Mennonite infants with MSUD died before 10 years of age from sudden brain herniation. Over a 16-year period, we have managed MSUD patients through over 170 hospitalizations for acute metabolic decompensations and have not witnessed a single death. Nevertheless, approximately 10% of these admissions were protracted and generated single-hospitalization costs greater than $100 000; single hospital bills have exceeded $450 000. Patient 8 suffered a nonlethal brain herniation that resulted in hospital costs in excess of $600 000 and left her with right-sided paraplegia, cognitive impairment and cortical blindness. This tragic clinical outcome is compounded by a lifetime requirement for costly supportive services and underscores a fear all MSUD families live with on a daily basis.
MSUD patients entering adulthood face daunting challenges on various fronts. First, metabolic control tends to deteriorate with age. This likely results from the combined effects of decreasing weight-adjusted leucine tolerance, decreased metabolic monitoring and waning parental and physician control over nutritional therapy. Leucine tolerance becomes very low (about 10 mg/kg/day) once the adult lean body mass has accrued. For practical purposes, this means that the adolescent and adult MSUD patient will only tolerate about 7–9 g of natural protein daily and be 90% dependent on synthetic medical foods for life. Social stigmata and serious health hazards accompany such a diet. We have documented widespread severe omega-3 fatty acid and zinc deficiencies in our patients (4), and surely they are at high risk for other iatrogenic nutritional deficiencies over the life span. Second, appropriate medical services for older patients do not exist. The large majority of adult MSUD patients in the United States and abroad are cared for by pediatricians. After such patients pass age 18 or 21 years, pediatric medical centers and insurance providers can stop providing specialized care, but the disease becomes neither less costly nor less dangerous. Third, the older MSUD patient population suffers from substantial neuropsychiatric morbidities that require treatment with psychoactive medications and impact work competency, earning potential, and the quality of cognitive and emotional life. This, in turn, can adversely affect dietary control. Many adult MSUD patients cannot maintain jobs that require sustained concentration, organization or memory and they are uniformly discouraged by long-term dietary constraints. Even under optimal circumstances, few classical MSUD patients can achieve full independence. The aforementioned arguments extend to a much larger aging population of individuals with phenylketonuria, partial ornithine transcarbamylase deficieny and other inborn metabolic errors, which similarly can be corrected with transplantation. The experience with MSUD may create new treatment opportunities for such patients.
Data presented here indicate that in terms of overall efficacy and protection from disease progression, liver transplantation is a reasonable treatment option for classical MSUD, similar in principle to its use in disorders such as familial hypercholesterolemia, primary hyperammonemia and Crigler-Najjar disease type 1 (33–36). However, donor livers are in short supply. Only 32% of 18 000 patients listed annually receive a graft, and the use of cadaveric livers to treat patients without primary liver failure engenders ethical judgments about a limited resource. However, young classical MSUD patients, like those with urea cycle disorders, qualify for high prioritization due to the neurological burden of their disease. Furthermore, liver transplantation was considered reasonable treatment by four state Medicaid agencies, five independent insurance carriers and the U.S. Military, all of whom reimbursed fully for the procedure. Finally, Khanna et al.† recently demonstrated that the liver of a classical MSUD patient can be successfully ‘domino’ transplanted into a recipient with no adverse consequences for peripheral amino acid homeostasis. It is possible that in the future, directed utilization of MSUD explants may help to resolve the controversy over allograft distribution.
The emergence of lymphoproliferative disease in patient 1, although successfully treated, underscores the fact that there are no easy solutions for patients living with MSUD. Nevertheless, the risks of perioperative mortality and postoperative complications were reviewed explicitly with families during the pre-transplant evaluation. Such knowledge did not dissuade parents during the decision phase, nor did it weaken their resolve when complications occurred during or after transplantation. Furthermore, long-term survival and quality of life post-transplant should continue to improve due to improved monitoring for EBV- and CMV-related complications (37), elimination of corticosteroids from immunosuppressive regimens and efforts to minimize immunosuppressive medication for individual patients (18,37).
The decision about medical versus surgical treatment for classical MSUD is a complicated one, and factors contributing to the decision will vary with each individual case. In our view, the parents of a child with such a dangerous and difficult problem are best informed to make comparative judgments about quality of life, health risk and financial burden, provided they receive accurate information regarding the risks and prognostic implications of various treatment options (38). If an individual with classical MSUD is to undergo the procedure, surgical planning should take into account the unpredictable nature of the disease. Pre- and post-transplantation complications occur (Table 3) and cannot be anticipated in an individual case. Thus, to optimize safety the procedure should be performed under protocol at a hospital with experienced surgical and metabolic specialists, and pharmacy and laboratory services ready to respond to contingencies in a timely manner.