controversial. From the age of 1 year onward, these children are often severely anorectic and most of the diet must be delivered by nocturnal gastric drip feeding ...
Eur J Pediatr (1999) 158 [Suppl 2]: S65 ± S69
Ó Springer-Verlag 1999
J. M. Saudubray á G. Touati á P. Delonlay á P. Jouvet á J. Schlenzig á C. Narcy J. Laurent á D. Rabier á P. Kamoun á D. Jan á Y. Revillon
Liver transplantation in propionic acidaemia
Abstract Despite the improvement in dietary therapy during the past 20 years, the overall outcome of severe forms of propionic acidaemia (PA) remains often disappointing. Good results can be obtained at a very high price in terms of medical attention, family burden and high cost. In most early onset forms of PA, the intake of natural protein must be rigidly restricted to 8±12 g/day for the ®rst 3 years of life, and then slowly increased to 15±20 g/day by the age of 6±8 years. Supplementation with a precursor-free aminoacid mixture to provide 1.5 g/kg protein per day is generally recommended, although remains controversial. From the age of 1 year onward, these children are often severely anorectic and most of the diet must be delivered by nocturnal gastric drip feeding or gastrostomy. Metronidazole is very eective in reducing the excretion of propionate metabolites derived from the gut. L-carnitine (50 to 100 mg/kg) is systematically given to promote propionylcarnitine synthesis and excretion. We report here a retrospective study of 33 patients with PA diagnosed during the last 20 years in our hospital. Of them, 2 have been liver transplanted. In these two patients who presented frequent severe and unexpected metabolic decompensations despite good compliance with the dietary therapy, orthotopic liver transplantation (OLT) was done at 7 and 9 years respectively. One child died 15 months after transplantation due to a severe lymphoproliferative disorder; the other child now aged 13.5 years is doing well. Despite a persistent methylcitrate excretion, she is under normal moderate daily protein intake (40±50 g/day) and still on carnitine supplementation. Interestingly, another patient who ®lled the criteria for OLT (very frequent and severe decompensations leading to frequent admissions to the intensive care unit despite excellent dietary management) was also placed on the list for OLT. From the time he was registered onward, he experienced no further episodes of metabolic decompensation, there was almost no interruption in his daily intake and he gained height and weight and developed well. He was ®nally removed from the list and is still doing very well 2 years thereafter. Correction of propionylCoA carboxylase de®ciency restricted to hepatic tissues seems to induce a change towards clinical normalisation and a milder biochemical phenotype. Liver transplanted PA patients still require slight protein restriction and carnitine treatment. We consider that at the moment OLT should only be performed in severe forms of PA, mostly characterised by frequent and unexpected episodes of metabolic decompensation despite good dietary therapy. However, a strict appreciation of these criteria is dicult. A more generalised indication for OLT in PA will require more information about the long-term outcome of transplanted patients. We should also await other alternatives like auxiliary partial OLT from living donors or transplantation of isolated allogenic hepatocytes, genetically modi®ed or not. J. M. Saudubray (&) á G. Touati á P. Delonlay á P. Jouvet J. Schlenzig á C. Narcy á J. Laurent Department of Paediatrics, Hopital Necker Enfant-Malades, 149 rue de Sevres, F-75743 Paris, France Tel.: +33-144-494852, Fax: +33-144-494850
D. Rabier á P. Kamoun Department of Biochemistry, Hopital Necker Enfants-Malades, Paris, France D. Jan á Y. Revillon Department of Paediatric Surgery, Hopital Necker Enfants-Malades, Paris, France
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Key words PropionylCoA carboxylase á Management of inborn errors of metabolism á Propionic acidaemia á Liver transplantation Abbreviations OLT orthotopic liver transplantation á PA propionic acidaemia Introduction
Despite the improvement in dietary therapy during the past 20 years, the overall outcome of severe forms of propionic acidaemia (PA) remains often disappointing. Treatment is primarily based on dietary protein restriction limiting propionic acid precursors while allowing for protein anabolism with supplementations of special amino acid mixtures free of respective amino acid precursors. In most early onset forms of PA, the intake of natural protein must be rigidly restricted to 8±10 g/day for the ®rst 3 years of life and then slowly increased to 15±20 g/day by the age of 6 to 8 years. Supplementation with a precursor-free amino acid mixture to meet 1.5 g/kg protein per day is generally recommended although remains controversial and presents the disadvantage of disturbing urinary urea excretion which is a very helpful tool to decide whether or not natural protein intake should be increased. Metronidazole is used for lowering the enteral source of propionate [25] and nocturnal tube feeding to diminish lipolysis due to fasting [22, 27, 28]. The aim of L-carnitine supplementation is to correct an existent de®ciency [3], restore the mitochondrial acylCoA/free CoA ratio and provide an ecient conjugate for the excretion of accumulated propionyl groups [2, 4]. Clinical prognosis and long-term outcome depend essentially on metabolic control in order to minimise accumulation of toxic metabolites. Nevertheless, the treatment of PA still poses considerable problems; despite intense medical eorts and family stress the prognosis for these patients, particularly those with onset in early neonatal life, is often disappointing. Good results however are obtained at a very high price in terms of medical attention, family burden and high cost [11, 19, 28]. In addition, some intercurrent complications like cardiomyopathy [13], pancreatitis [9] and central nervous system injury [10] can be observed unexpectedly despite an apparently correct management [18, 19, 24]. Given that isoleucine and valine (the two main amino acid precursors of propionate) undergo a splanchnic extraction and are mainly recovered after peripheral transamination to branched chain ketoacids by the liver for further oxidation [7, 12, 14, 15], liver transplantation for PA was ®rst attempted in 1992. The 26-month-old recipient was retransplanted because of grave failure due to surgical complications and died of heart failure 3 days later [16]. After having observed a dramatic improvement of branched chain amino acid levels in a 7-year-old patient with classical maple syrup urine disease who was liver transplanted for terminal liver failure attributed to
hepatitis A virus infection [17, 20], we performed othotopic liver transplantation (OLT) in two children aected with a severe form of PA [23]. Here we present a retrospective study of 33 patients with PA diagnosed during the last 20 years in our hospital, treated by classical dietary therapy or OLT. Patients and methods Patients The study group consisted of 25 patients with early onset type of disease and eight patients with a late onset form. All were diagnosed by speci®c organic acid pro®le and propionyl-CoA carboxylase determination in cultured ®broblasts. In the early onset group, the most prominent symptoms started within 3 weeks after birth and encompassed feeding diculties, vomiting, hyperventilation, dehydration and hypothermia. The neurological features were characterised by slow reactivity, pedalling movements, axial hypotonia and limb hypertonia with large amplitude tremors and myoclonic jerks. A profound coma was present in 50% of the patients. In the late onset group, clinical features diered in many aspects from the early onset patients. Three patients had a mainly gastro-enterological presentation consisting of vomiting and feeding diculties with concomitent failure to thrive and malnutrition. One patient was thought to have food intolerance. These symptoms became obvious after 3±6 months of life. Another patient presented with a predominantly neurological picture. Three patients presented with ketoacidotic coma at the age of 3 years. OLT was performed in two patients, a 7-year-old boy and a 9 year-old girl, diagnosed with a severe neonatal form of PA with high risk of metabolic decompensation. In both cases, the metabolic liver functions recovered within 12 post-operative hours. No clinical symptoms of propionic acid toxicity, metabolic acidosis, severe hyperammonaemia, hyperglycinaemia or haematological abnormalities were observed. In both cases, insulin dependent diabetes mellitus occurred early after OLT (persisting in the boy's case). Severe post-transplantation complications were observed (acute rejection and cytomegalovirus infection) in both patients which did not trigger metabolic decompensation. Methods To study dierent aspects of outcome, we used the same methods as in our patients with methylmalonic acidaemia [27, 28]. A ``disability scale'' was applied which contains seven subscales subdivided into four grades: normal (good to very good), minor (fair), intermediate (acceptable) and major abnormalities (bad). Neuromotor outcome expressed the presence or absence of neurological abnormalities and the degree of motor development. Mental outcome re¯ected the intellectual development of the child as measured by psychological testing and the degree of schooling. Psychological outcome considered the behaviour or status of the child. Visceral outcome pointed to the involvement of heart, liver, kidney or pancreas. Sensory outcome re¯ected the presence or absence of visual or hearing problems. Social outcome described the presence of social and familial problems such as problems in socio-cultural adaptation, parental diculties in coping with the disease, marriage disturbances, poor family circumstances and/or the need for placing the child in a centre for
S67 special care. Nutritional outcome was re¯ected by weight and height, and to a lesser degree by head circumference.
Results
A total of 18 patients died (Fig. 1), 12 in the immediate neonatal period. In the six others, death occurred between 2 and 11 years during an episode of acute and irreversible decompensation. Among these six patients, four aged 5 to 11 years had normal growth and a good Fig. 1 PA: outcome of 18 deceased patients
Fig. 2 PA: outcome of 15 living patients
to acceptable neurological and psychomotor development when they died. In this group, all patients were aected with severe neonatal or early infantile forms. The 15 living patients are aged 1.5 to 30 years, median 7 years (Fig. 2). Five patients (aged 7 to 30 years) are aected with late onset forms of whom two who had initial symptoms before 1 year of age, are mentally and neurologically handicapped, and three, who presented at the age of 3 years, are in good to fair condition. Of the ten patients with the early type of disease aged 1.5 to 12 years (median 5 years), only one patient aged 5 years
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is mentally handicapped. All other nine patients still have a normal development, however, two have mild asymptomatic myocardiopathy only detectable by systematic echocardiography. Of the two patients who were liver transplanted, the boy developed chronic rejection and vanishing bile duct syndrome due to incomplete hepatic arterial thrombosis. He required permanent inpatient care with chronic hyperammonaemia and neurological sequelae involving the basal ganglia, and died 15 months after OLT due to a severe lymphoproliferative disorder induced by FK506. The other child (a girl), now aged 14 years, is doing well although she is an asymptomatic carrier for hepatitis B. She left hospital after 2 months with almost no dietary protein restriction (40 g protein/day). Urinary urea excretion and daily protein intake increased after liver transplantation (Fig. 3). Propionylglycine and tiglylglycine disappeared immediately after OLT. Urinary methylcitrate and 3hydroxypropionate remained at concentrations corresponding to those before OLT. However, the total of all characteristic metabolites of organic acid analysis was reduced to 50%±60% of the values before OLT in both patients. Propionylcarnitine was still detected at signi®cant concentrations. Plasma odd-chain fatty acid concentrations decreased continuously after OLT only in the girl's case. Tissue of both transplanted livers showed increased odd-chain fatty acid concentrations 9 and 15 months after OLT respectively in both patients [23]. Her moderate cardiomyopathy which was present before OLT remains but is improving slightly. Discussion
Liver transplantation in inherited disorders of metabolism is acceptable when phenotypic and functional cure is achieved [29]. This aim was only partially reached in our transplanted PA patients: the clinical phenotype was corrected and metabolic decompensations did not recur in either patient after OLT. There are practically no dietary protein restrictions and lifestyle has been completely normalised in the girl's case, de®ning her as ``cured''. Nonetheless, the biochemical phenotype still shows the typical pattern of PA with a persistent excretion of respective urinary metabolites because the metabolic error as only been corrected in liver tissue and the liver is obviously not able to clear all extra-hepatic breakdown products of precursor catabolism. Thus, functional cure is only partially complete. The known toxicity of certain metabolites renders a prognosis of phenotypic evolution impossible; hence, the long-term eects of elevated concentrations of these metabolites and especially methylcitrate on visceral tissues, are not predictable and such typical complications in patients with PA as cardiomyopathy, neurological impairment and pancreatic malformation might occur in the future. Correction of propionyl-CoA carboxylase de®ciency restricted to hepatic tissues seems to induce a change towards clinical normalisation and a milder biochemical
Fig. 3 Metabolite excretion after liver transplantation in a patient with PA. (from [23] with publishers permission)
phenotype. Liver transplanted PA patients should eventually still require a slight protein restriction and carnitine treatment after OLT. We consider that, at the moment, OLT should only be performed in severe forms of PA, characterised by frequent and unexpected decompensations despite good dietetary therapy. However, a strict appreciation of these criteria is dicult, mostly in de®ning what the term ``good dietary therapy'' actually means!. This is illustrated by our patient now aged 9 years old (Fig. 2). This patient ful®lled the criteria for OLT (very frequent and severe decompensations leading to frequent admissions in intensive care unit despite excellent dietary management) and was also placed on the list for OLT. From that time, he never experienced any further episodes of metabolic decompensation, there was almost no interruption in his daily intake, he gained height and weight and has developed well. He was ®nally removed from the list and is still doing well 2 years later.
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A more generalised indication of OLT in PA will require more information about the long-term outcome of transplanted patients. We should also await other alternatives like auxiliary partial OLT from living donors [5, 21, 26] or transplantation of isolated allogenic hepatocytes [1, 6, 8]. References 1. Arkadopoulos N, Lilja H, Suh KS, Detry O, Mullon C, Demetriou AA, Rozga J (1997) Transplantation of isolated hepatocytes prolongs survival and improves blood chemistry in anhepatic rats. Hepatology (abstract) 26:252A 2. Burns SP, Iles RA, Saudubray JM, Chalmers RA (1996) Propionylcarnitine excretion is not aected by metronidazole administration to patients with disorders of propionate metabolism. Eur J Pediatr 155:31±35 3. Chalmers RA, Roe CR, Stacey TE, Hoppel CL (1984) Urinary excretion of L-carnitine and acylcarnitines by patients with disorders of organic acid metabolism:evidence for secondary insuciency of L-carnitine. Pediatr Res 18:1325±1328 4. Chalmers RA, Roe CR, Tracey BM, Stacey TE, Hoppel CL, Millington DS (1984) Secondary carnitine insuciency in disorders of organic acid metabolism:modulation of acylCoA/CoA ratios by L-carnitine in vivo. Biochem Soc Trans 11:724±725 5. Egawa H, Tanaka K, Inomata Y, Uemoto S, Okajima H, Satomura K, Kiuchi T, Yabe S, Nishizawa H, Yamaoka Y (1996) Auxiliary partial orthotopic liver transplantation from a living related donor:a report of two cases. Transplant Proc 2:1072 6. Fox IJ, Roy Chowdhury J, Kaufman SS, Roy Chowdhury N, Kostrubsky VE, Sauter B, Strom SC (1997) Transplantation of isolated allogenic hepatocytes in a patient with Crigler-Najjar syndrome type 1 resulted in excretion of bilirubin glucuronides in bile and partial amelioration of hyperbilirubinemia (abstract). Hepatology 26:176A 7. Hoerr RA, Matthews DE, Bier DM, Young VR (1991) Leucine kinetics from [2H3] and [13C]leucine infused simultaneously by gut and vein. Am J Physiol 263:E111±E117 8. Ilan Y, Sauter B, Roy Chowdhury N, Groguett G, Reddy BVN, Davidson A, Horwithz MS, Roy Chowdhury J (1997) Expression of adenoviral E3 gene products in normal rat hepatocytes prevents their rejection upon transplantation into allogenic Gunn rats (abstract). Hepatology 26:251A 9. Kahler SG, Sherwood WG, Woolf D, Lawless ST, Zaritsky A, Bonham J, Taylor CJ, Clarke JTR, Durie P, Leonard JV (1994) Pancreatitis in patients with organic acidemias. J Pediatr 124:239±243 10. Korf B, Wallman JK, Levy HL (1986) Bilateral lucency of the globus pallidus complicating methylmalonic acidemia. Ann Neurol 20:363±366 11. Lehnert W, Sperl W, Suormala T, Baumgartner ER (1994) Propionic acidaemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients. Eur J Pediatr 153[Suppl 1]: S68±S80 12. Liversey G, Lund P (1980) Enzymatic determination of branched-chain amino acid and 2-oxoacids in rat tissues. Biochem J 188:705±713 13. Masoud AF, Leonard JV (1993) Cardiomyopathy in propionic acidaemia. Eur J Pediatr 152:441±445 14. Matthews DE, Bier DM, Rennie MJ (1981) Regulation of leucine metabolism in man: a stable isotope study. Science 214:1129±1131
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