Liver Transplantation for Propionic and Methylmalonic Acidemias

Jerry Vockley, M.D., Ph.D.

Professor of Pediatrics, University of Pittsburgh School of Medicine
Professor of Human Genetics, University of Pittsburgh Graduate School of Public Health
Chief of Medical Genetics, Children’s Hospital of Pittsburgh

Liver transplantation (LTx) was initially developed as a therapy for liver diseases known to be associated with a high near-term risk of death. However, LTx for inborn metabolic diseases is based upon a different set of criteria. It is of use for any disorder in which toxic metabolites can affect any organs through the systemic circulation. In this setting, a transplanted liver can correct metabolic balance in other organs. As risks of the procedure have decreased and post-operative outcomes have improved, LTx has evolved into an attractive approach for a growing number of metabolic diseases in which the procedure can be life-improving rather than strictly life-saving, blurring the line between standard medical management and a more aggressive surgical therapy. In this setting, the risks and benefits of LTx must be placed in the context of current and potential medical advances. Ultimately, it is critical to have a relatively complete understanding of the biology of the disease to predict the potential impact of LTx on the body.

Propionic acidemia (PA) and primary methylmalonic academia (MMA) are organic acidemias resulting from defective breakdown of the amino acids isoleucine, valine, methionine, and threonine due to mutations in the genes for propionyl-CoA carboxylase or methylmalonyl-CoA mutase, respectively. MMA is additionally present in several inborn errors of cobalamin (vitamin B12) metabolism. Severe forms typically present with severe hyperammonemia, ketoacidosis, and neurological problems, including coma very soon after birth. To minimize neurological sequelae, intensive clinical management, including aggressive treatment such as dialysis or hemofiltration, is required. Despite early diagnosis and maximal metabolic control, many patients develop considerable neurological, psychological, cardiac, and renal complications [36, 39].

17 cases of transplant of propionic and 35 of methylmalonic acidemia have been reported in the medical literature. Follow up ranged from 2-120 months. Clinical experience remains relatively limited but is encouraging. Successful LTx appears to improve metabolic control, resulting in better quality of life with less strict dietary restrictions, and positive effects on development. Heart failure has improved if present. However, other consequences of the diseases can still occur, including CNS complications such as metabolic stroke its incidence and severity of metabolic strokes is dramatically decreased. Renal failure can still occur in MMA and so a combined liver kidney transplant should be considered in this condition, especially if renal disease is already present. Benefits must also be weighed against the risks of long term immunosuppression.

The use of solid organ LTx to treat liver-based metabolic disorders is limited by a severe shortage of donor organs, the risks associated with major surgery, and the low, but real, long-term risk of graft loss from rejection. Hepatocyte transplantation holds promise as an alternative to organ transplantation, and numerous animal studies indicate that transplants of isolated liver cells can correct metabolic deficiencies of the liver. Clinically, the procedure involves isolation of cells from livers rejected for solid organ transplant, which are then transplanted via the portal vascular system into the liver [75]. This procedure is far less intrusive than replacement of the liver. Since the native liver is not removed, the transplanted hepatocytes need only improve the single enzyme deficiency and need not replace all hepatic functions. Since even a full liver transplant doesn’t reduce metabolite concentration to normal in blood in patients with PA and MMA, the role of hepatocyte transplant remains to be demonstrated.

The efficacy of LTx for metabolic diseases has been demonstrated through single- and multi-center reviews as well as in reviews of national databases, achieving a >82% survival rate at 10 years. The single center experience at Children’s Hospital of Pittsburgh provides outcomes over thirty years. In that time, two-hundred and eighty-five children underwent pediatric LTx for metabolic indications. The mean age at transplantation was 7.6 years (16 days to 23 years). Forty-three children underwent re-LTx at a mean of 2.3 years (2 days to 18.2 years) post-transplant. While historically, 70% of transplanted patients are still alive, results over the last 10-13 years have demonstrated significant improvement in survival. Of 100 patients receiving transplants over the past decade at CHP, only three died (two of infection and one of suicide) and only one required retransplantation, with patient survival over the past 10 years currently at 97%. Longer follow-up will be needed to recognize late appearing concerns in patients and families. Immunosuppression and current research on how to reduce its impact is a major component of the program in Pittsburgh. Clearly, clinical decision-making is best undertaken by a discussion of the best available long term results of transplant in the context of a patients specific circumstances.

The shortage of available livers for transplantation is an important issue to consider with the use of LTx for metabolic disorders. While the use of living donors is becoming increasingly popular, a potential complicating issue is that parents of children with PA and MMA are carriers for the conditions, and there is a 2/3 chance that their siblings are carriers. However, since parents have no symptoms, 50% of normal activity is likely to be sufficient to improve metabolic control.

In summary, LTx has been revolutionary and life-saving for some metabolic disorders. Initially viewed as a rescue procedure for such conditions, the risk of death or disability due to many inborn errors of metabolism now outweighs that of a transplant. Thus the role of transplant in treatment of PA and MMA will likely continue to evolve and increase.

From the Fall 2014 OAA Newsletter

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