Propionic acidemia (PA) is a rare metabolic disorder caused by a deficiency in propionyl-CoA carboxylase (PCC) activity. The hallmark is recurrent metabolic acidosis usually precipitated by excessive protein ingestion or infection. The mainstay of conservative management is dietary protein restriction, metronidazole and/or l-carnitine supplements. Despite this, overall outcome remains disappointing with relapsing episodes of metabolic decompensation and long-term complications, mainly developmental retardation and cardiomyopathy.
Liver transplantation (LT) is presently the only treatment modality with an important role in the management of PA complications (1–3). Worldwide experience is, however, limited (Table 1), and potential benefits of LT must be weighed against perioperative morbidity and long-term immunosupression. Herein we report our experience concerning LT in PA highlighting the peritransplant management.
Patient 1: A boy of Moroccan origin, first child of healthy consanguineous couple (first-degree cousins), developed metabolic acidosis and hyperammonemia at age 5 days. The diagnosis as having PA was confirmed by urinary organic acid analysis and PCC activity of skin fibroblasts. Tube feeding with a protein-restricted diet (0.5 g · kg−1 · day−1) and administration of l-carnitine were initiated. Despite appropriate treatment, several episodes of metabolic decompensation occurred in the subsequent years. Although maintaining a nearly normal mental development at age of 5 years, the echocardiography revealed a dilated left ventricle (4.03 cm, +2.15SD) with preserved systolic function. Angiotensin-converting enzyme inhibitor and digoxin were initiated, and LT was proposed to minimize the risk of further cardiac decompensation. Elective orthotopic LT was successfully performed at 12.5 years.
Patient 2: A girl of Turkish origin, born at 33 weeks of gestation, was diagnosed as having PA based on the Guthrie test and then confirmed by PCC activity. Standard medical treatment was promptly started. Her neonatal period was unremarkable, but at 10 months of age she had a metabolic and cardiac decompensation (ejection fraction of 48%) in the context of respiratory syncytial virus bronchiolitis. Her cardiac function then stabilized on digoxin treatment. Failure to thrive and metabolic decompensations in the context of alimentary difficulties led to enteral feeding by gastrostomy tube starting at 18 months. At 4.5 years, despite reasonable metabolic control, we assisted to another cardiac deterioration (ejection fraction 42%). At this time, her growth was also severely delayed with a height of 91.3 cm (mean −2.1SD). Her developmental quotient for cognition/adaptation was lower than the controls. Orthotopic LT was proposed and successfully performed at 5.5 years.
PERI- AND POST-TRANSPLANT MANAGEMENT
After the diagnosis and before LT, the medical management included low-protein diet and administration of metronidazole (10–20 mg · kg−1 · day−1), sodium benzoate (250 mg · kg−1 · day−1), and l-carnitine (200–300 mg · kg−1 · day−1). During the perioperative fasting period, the recipients started an infusion of 10% dextrose and sodium bicarbonate at 1.5 times the normal maintenance rate by weight. Induction of anesthesia was provided by thiopental and muscle relaxation was provided by vecuronium. They were monitored for blood glucose levels and acid–base balance perioperatively and until they were able to tolerate oral intake. In both patients, immediate postoperative course was uneventful with no episodes of metabolic or hepatic decompensation. Table 2 shows a profile of the recipients involved in this report.
During the follow-up period there were no metabolic decompensations, allowing for progressive diet liberalization without need for any supplements other than carnitine. Their only dietary constraints included avoidance of high-protein foods (eg, meat, dairy products, and eggs). The patients’ general clinical condition improved remarkably, and there was no further neurologic decline. We also assisted to a stabilization and then to a progressive resolution of cardiomyopathy. Biochemically, the improvement was not so significant, but the levels of serum propionyl carnitine (C3) were lower and serum propionyl carnitine/serum acetylcarnitine ratio (C3/C2) decreased in both patients, and to less than 1 in patient 2.
LT has been viewed as one of the potential treatment modalities for PA because liver is the major site of branched-chain amino acid metabolism and subsequent propionic acid production. The worldwide experience in treating PA with LT is limited. Since the first attempted in 1992 (4), a total of 20 pediatric patients with PA underwent LT (Table 1). Early reports showed unsatisfactory outcomes marked by significant mortality and transplantation-related complications. In 2001, Leonard et al (1) reported attempts at LT from cadaveric, which have been hampered by life-threatening perioperative complications with a reported 2-year survival of <50%, but a better quality of life for the survivors. Five years later, Barshes et al (2) showed an overall patient survival rate of 72.2% at 1 year after living donor LT.
During the procedure, these patients are prone to complications related to surgery and anesthetic management (5). One of the main concerns is related to medication choices. The use of inappropriate anesthetics may precipitate and/or aggravate metabolic acidosis. Drugs metabolized to propionic acid, odd-chain organic acids, odd-chain alcohols, or odd-chain fatty acids should be avoided. The anesthetic induction was made with thiopental as propofol should be avoided, because a small portion of the fats included may be metabolized to propionic acid. Also, muscle relaxants metabolized by ester hydrolysis (succinylcholine, cisatracurium, and atracurium) should not be used because their metabolites include odd-chain organic molecules (6). Verocuronium is safe, and therefore it was used. In addition, medications derived from propionic acid such as ibuprofen and naproxen should be avoided as they add an extra propionic acid load to the body.
During maintenance of anesthesia, events such as hypoxemia, dehydration, hypotension, and acidosis should be avoided. During the fasting period, patients require IV fluids containing dextrose and sodium bicarbonate to suppress protein catabolism and subsequent acidosis. Supporting Romano et al (7), we also suggest that adequate protein restriction and carnitine administration should be maintained during peri- and early postoperative period as a precaution against metabolic decompensation and possible late complications.
Clinical prognosis and long-term outcome depend essentially on the metabolic control to minimize accumulation of toxic metabolites. The findings in our 2 recipients are according to the most recent reports suggesting that LT has an important role in this setting, leading to clinical improvement, reflected by better feeding, fewer episodes of metabolic acidosis; hampering of neurocognitive decline, and improving cardiomyopathy (8).
Accumulated cases from the literature also demonstrate that LT often obviates the need for dietary restriction and medical management. In fact, our cases achieved a clinical resolution of metabolic derangement and better quality of life with an average natural protein ingestion of 1 mg · kg−1 · day−1. Serum propionylcarnitine levels, however, did not decrease markedly, mostly owing to the presence of extrahepatic sources of propionic acid (ie, the gut and the central nervous system). Thus, in addition to addressing the biochemical disorder, drastically reducing the incidence of hyperammonemia, functional cure is only partially complete making the role of LT not straightforward. In less severe cases, parents and physicians are balanced between conservative management and LT, the procedure in which access remains highly limited by donor shortage.
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