American Journal of Transplantation 2015; 15: 786–791 Wiley Periodicals Inc.
C
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13027
Brief Communication
Early and Late Complications After Liver Transplantation for Propionic Acidemia in Children: A Two Centers Study F. Charbit-Henrion1, F. Lacaille2, P. McKiernan3, M. Girard2, P. de Lonlay4, V. Valayannopoulos4, C. Ottolenghi5, A. Chakrapani6, M. Preece7, K. Sharif3, C. Chardot8, P. Hubert9 and L. Dupic9 1 Laboratory of Intestinal Immunity, Unite´ INSERM UMR1163, Institut IMAGINE, Paris, France 2 Service de Gastroente´rologie-He´patologie-Nutrition Pe´diatrique, Hoˆpital Necker-Enfants Malades, Paris, France 3 Liver Unit, Birmingham Children’s Hospital, Birmingham, United Kingdom 4 Service de Maladies Me´taboliques, Hoˆpital NeckerEnfants Malades, Paris, France 5 Service de Biochimie Me´tabolomique et Prote´omique, Hoˆpital Necker-Enfants Malades, Paris, France 6 Inherited Metabolic Disease Unit, Birmingham Children’s Hospital, Birmingham, United Kingdom 7 Inherited Metabolic Disease Laboratory, Birmingham Children’s Hospital, Birmingham, United Kingdom 8 Service de Chirurgie Visce´rale, Hoˆpital Necker-Enfants Malades, Paris, France 9 Service de Re´animation Polyvalente et soins continus me´dico-chirurgicaux, Hoˆpital Necker-Enfants Malades, Paris, France Corresponding author: Fabienne Charbit-Henrion, [email protected]
Propionic acidemia (PA) is a severe metabolic disorder with cardiac and neurologic complications and a poor quality of life. Liver transplantation (LT) was thus proposed in PA to increase enzyme activity. We studied retrospectively LT in PA in two European centers. Twelve patients underwent 17 LTs between 1991 and 2013. They developed severe, unusual and unexpected complications, with high mortality (58%). When present, the cardiomyopathy resolved and no acute metabolic decompensation occurred allowing dietary relaxation. Renal failure was present in half of the patients before LT and worsened in all of them. We suggest that cardiac and renal functions should be assessed before LT and monitored closely afterward. A renal sparing immunosuppression should be used. We speculate that some complications may be related to accumulated toxicity of the disease and that earlier LT could prevent some of these consequences. As kidney transplantation has been performed successfully in methylmalonic acidemia, a metabolic disease in the 786
same biochemical pathway, the choice of the organ to transplant could be further discussed. Abbreviations: BCH, Birmingham Children’s Hospital; eGFR, estimated GFR; GFR, glomerular filtration rate; HAT, hepatic artery thrombosis; ICU, intensive care unit; IQR, interquartile range (25–75%); LT, liver transplantation; mGFR, measured GFR; MMA, methyl-malonic acidemia; NCK, Necker-Enfants Malades Hospital; OA, organic acidemias; PA, propionic acidemia; PCC, propionyl-CoA carboxylase; PTLD, posttransplantation lymphoproliferative disorder Received 29 May 2014, revised 10 September 2014 and accepted for publication 14 September 2014
Introduction Organic acidemias (OA) are severe inborn errors of the catabolism of branched-chain amino acids and oddnumbered chain fatty acids. Propionic acidemia (PA; OMIM #606054) and methylmalonic acidemia (MMA) are the most frequent OA. PA is an autosomal recessive disorder in which the activity of propionyl-CoA carboxylase (PCC; EC 6.4.1.3) is ubiquitously deficient. PCC converts propionyl-CoA into methylmalonyl-CoA which generates components used by the mitochondrial respiratory chain. PCC deficiency leads to the accumulation in the mitochondria of propionyl-CoA and its metabolic by-products. The incidence of PA is estimated around 1 per 100,000 live births in Caucasian population. PA is usually diagnosed in the first weeks of life with symptoms of intoxication, such as hypotonia and vomiting, leading to dehydration, coma, ketoacidosis and hyperammonemia (1,2). The mortality in PA was previously reported as high as 40% (3,4), but even with contemporary management in expert centers (5) it remains about 17%, with half of the deaths occurring in neonates. The main complications are neurological and cardiac. Delayed cognitive development is observed in 61% of patients by 3 years of age (6). Dilated cardiomyopathy is described in 23% of patients with a mean age at onset of
Liver Transplantation in Propionic Acidemia
7 years (7). These complications may arise despite good compliance with a strict low-protein diet. The treatment aims at managing protein intake, avoiding catabolism and reducing propionate production from the gut flora. Patients need aggressive management during acute metabolic decompensations which may be frequent in the first years of life (7,8). Thus, the intensity of the medical management combined with frequent hospitalizations significantly impact the quality of life of those children and their families. As liver transplantation (LT) in children now offers an 80% 10-year survival (9), it has been proposed as a treatment for PA to restore some enzyme activity. The first successful LT in a PA patient was performed in 1993 at Necker-Enfants Malades Hospital (NCK) in Paris (10) (patient 3 [P3]). We have previously shown that the PA-associated cardiomyopathy is reversible after LT (7) but the neurocognitive sequelae are probably irreversible. The overall mortality rate following LT in PA has been reported around 30% (11) which is significantly higher than for other indications (10–20%) (9). We present here the experience of our two institutions (Birmingham Children’s Hospital [BCH], UK and NCK, Paris, France) of LT in PA, in order to better delineate the indications and complications, and discuss the possible optimization of the procedure in timing and management.
Patients and Methods The medical files of patients who underwent LT in BCH and NCK since 1984 were reviewed. The patients are labeled according to their date of first LT. The following data were recorded: metabolic disease (age and symptoms at onset, medical treatment prior to the LT, biochemical data, number of metabolic decompensation, protein restriction), pre-LT assessment (renal function, cardiac evaluation, liver function), early management in intensive care unit (ICU) (early complications, length of stay, immunosuppression, and biochemical results), and long-term follow-up (mortality, late complications, neurological outcome, biochemical data, protein restriction, metabolic decompensation). When possible, median and interquartile range (IQR, i.e. 25–75%) are calculated.
inuline clearance technique, and expressed as mL/min/1.73 m2. Renal dysfunction was defined as GFR < 90 mL/min/1.73 m2.
Results Twelve patients (6 boys, 7 from BCH) born between 1984 and 2005 underwent 17 LTs, with a median follow-up of 17 years. PA was diagnosed in the first month of life (median 5 days, IQR: 3–20 days), with symptoms of intoxication such as coma, hypotonia, ketoacidosis and hyperammonemia, or after targeted screening where a previous sibling was affected for P5 and P9. Medical management included a strict low-protein diet (0.6–1.2 g/ kg/day) and L-Carnitine supplementation. Antibiotics, biotin supplementation and sodium benzoate were used in individual cases. Seven patients required nasogastric or gastrostomy tube feeding in order to achieve optimal caloric intake and reduce night catabolism. Before LT, all patients had a normal height and weight for their age. Four patients had severe osteopenia (P2, P10, P11, P12) evaluated by radiological criteria (P2, P11) or absorptiometry (P10: Z-score 2.6; P12: Z-score 5.8) with multiple fractures (P11, P12). Before LT, the median number of metabolic decompensations was six episodes per year per patient (IQR: 4.5–7) (Table 1). Median levels of propionate metabolites was 9 mM/mM of creatinine for the 3-hydroxypropionate, and 222 mM/mM of creatinine for the methylcitrate (P8, P9, P11; results 6 months before LT). All patients underwent heart ultrasonography during their pre-LT evaluation. Three patients displayed cardiomyopathy and were further evaluated with a cardiac catheterization: blood pressure values were normal in all three patients, and the clamping test of the inferior vena cava was normal except for P10. None of the patients had pulmonary symptoms. The renal function was assessed before LT in eight patients, with a median GFR of 86 mL/min/1.73 m2 (IQR: 77.5–104).
The accumulation of specific propionate metabolites in urine (3-hydroxypropionate, propionyl glycine, tiglylglycine and methylcitrate) was measured by gas chromatography–mass spectrometry at NCK, before and after LT. At BCH, organic acid analysis was undertaken using a semi-quantitative method that was in use at that time.
LT was performed between 1991 and 2013. The indications were frequent metabolic decompensations (eight patients), cardiomyopathy (three patients), pre-emptive treatment (two patients), and cirrhosis (one patient). Four patients required a retransplantation: two for biliary cirrhosis secondary to hepatic artery thrombosis (HAT, P6: delay 5 years and 4 months for each retransplantation; P10: delay 4 years), one for primary nonfunction of the graft (P1: delay 3 days), one for hepatic dysfunction after HAT (P8: delay 7 days). The median age at first transplantation was 3.2 years (range IQR: 1.6–6.8 years) (Table 1).
GFR was either estimated (eGFR) using the plasma creatinine levels and the Schwartz formula (12), or measured (mGFR) via radionuclide, iohexol or
All patients received a graft from a deceased donor. Twelve out of 17 LT were performed with a reduced graft (Table 1).
Acute metabolic decompensations are defined as ketoacidosis requiring emergency treatment and hospitalization. The diagnosis of hypokinetic dilated cardiomyopathy was made by echocardiography (dilated cardiac muscle, thin walls, ejection fraction
C
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13027
Brief Communication
Early and Late Complications After Liver Transplantation for Propionic Acidemia in Children: A Two Centers Study F. Charbit-Henrion1, F. Lacaille2, P. McKiernan3, M. Girard2, P. de Lonlay4, V. Valayannopoulos4, C. Ottolenghi5, A. Chakrapani6, M. Preece7, K. Sharif3, C. Chardot8, P. Hubert9 and L. Dupic9 1 Laboratory of Intestinal Immunity, Unite´ INSERM UMR1163, Institut IMAGINE, Paris, France 2 Service de Gastroente´rologie-He´patologie-Nutrition Pe´diatrique, Hoˆpital Necker-Enfants Malades, Paris, France 3 Liver Unit, Birmingham Children’s Hospital, Birmingham, United Kingdom 4 Service de Maladies Me´taboliques, Hoˆpital NeckerEnfants Malades, Paris, France 5 Service de Biochimie Me´tabolomique et Prote´omique, Hoˆpital Necker-Enfants Malades, Paris, France 6 Inherited Metabolic Disease Unit, Birmingham Children’s Hospital, Birmingham, United Kingdom 7 Inherited Metabolic Disease Laboratory, Birmingham Children’s Hospital, Birmingham, United Kingdom 8 Service de Chirurgie Visce´rale, Hoˆpital Necker-Enfants Malades, Paris, France 9 Service de Re´animation Polyvalente et soins continus me´dico-chirurgicaux, Hoˆpital Necker-Enfants Malades, Paris, France Corresponding author: Fabienne Charbit-Henrion, [email protected]
Propionic acidemia (PA) is a severe metabolic disorder with cardiac and neurologic complications and a poor quality of life. Liver transplantation (LT) was thus proposed in PA to increase enzyme activity. We studied retrospectively LT in PA in two European centers. Twelve patients underwent 17 LTs between 1991 and 2013. They developed severe, unusual and unexpected complications, with high mortality (58%). When present, the cardiomyopathy resolved and no acute metabolic decompensation occurred allowing dietary relaxation. Renal failure was present in half of the patients before LT and worsened in all of them. We suggest that cardiac and renal functions should be assessed before LT and monitored closely afterward. A renal sparing immunosuppression should be used. We speculate that some complications may be related to accumulated toxicity of the disease and that earlier LT could prevent some of these consequences. As kidney transplantation has been performed successfully in methylmalonic acidemia, a metabolic disease in the 786
same biochemical pathway, the choice of the organ to transplant could be further discussed. Abbreviations: BCH, Birmingham Children’s Hospital; eGFR, estimated GFR; GFR, glomerular filtration rate; HAT, hepatic artery thrombosis; ICU, intensive care unit; IQR, interquartile range (25–75%); LT, liver transplantation; mGFR, measured GFR; MMA, methyl-malonic acidemia; NCK, Necker-Enfants Malades Hospital; OA, organic acidemias; PA, propionic acidemia; PCC, propionyl-CoA carboxylase; PTLD, posttransplantation lymphoproliferative disorder Received 29 May 2014, revised 10 September 2014 and accepted for publication 14 September 2014
Introduction Organic acidemias (OA) are severe inborn errors of the catabolism of branched-chain amino acids and oddnumbered chain fatty acids. Propionic acidemia (PA; OMIM #606054) and methylmalonic acidemia (MMA) are the most frequent OA. PA is an autosomal recessive disorder in which the activity of propionyl-CoA carboxylase (PCC; EC 6.4.1.3) is ubiquitously deficient. PCC converts propionyl-CoA into methylmalonyl-CoA which generates components used by the mitochondrial respiratory chain. PCC deficiency leads to the accumulation in the mitochondria of propionyl-CoA and its metabolic by-products. The incidence of PA is estimated around 1 per 100,000 live births in Caucasian population. PA is usually diagnosed in the first weeks of life with symptoms of intoxication, such as hypotonia and vomiting, leading to dehydration, coma, ketoacidosis and hyperammonemia (1,2). The mortality in PA was previously reported as high as 40% (3,4), but even with contemporary management in expert centers (5) it remains about 17%, with half of the deaths occurring in neonates. The main complications are neurological and cardiac. Delayed cognitive development is observed in 61% of patients by 3 years of age (6). Dilated cardiomyopathy is described in 23% of patients with a mean age at onset of
Liver Transplantation in Propionic Acidemia
7 years (7). These complications may arise despite good compliance with a strict low-protein diet. The treatment aims at managing protein intake, avoiding catabolism and reducing propionate production from the gut flora. Patients need aggressive management during acute metabolic decompensations which may be frequent in the first years of life (7,8). Thus, the intensity of the medical management combined with frequent hospitalizations significantly impact the quality of life of those children and their families. As liver transplantation (LT) in children now offers an 80% 10-year survival (9), it has been proposed as a treatment for PA to restore some enzyme activity. The first successful LT in a PA patient was performed in 1993 at Necker-Enfants Malades Hospital (NCK) in Paris (10) (patient 3 [P3]). We have previously shown that the PA-associated cardiomyopathy is reversible after LT (7) but the neurocognitive sequelae are probably irreversible. The overall mortality rate following LT in PA has been reported around 30% (11) which is significantly higher than for other indications (10–20%) (9). We present here the experience of our two institutions (Birmingham Children’s Hospital [BCH], UK and NCK, Paris, France) of LT in PA, in order to better delineate the indications and complications, and discuss the possible optimization of the procedure in timing and management.
Patients and Methods The medical files of patients who underwent LT in BCH and NCK since 1984 were reviewed. The patients are labeled according to their date of first LT. The following data were recorded: metabolic disease (age and symptoms at onset, medical treatment prior to the LT, biochemical data, number of metabolic decompensation, protein restriction), pre-LT assessment (renal function, cardiac evaluation, liver function), early management in intensive care unit (ICU) (early complications, length of stay, immunosuppression, and biochemical results), and long-term follow-up (mortality, late complications, neurological outcome, biochemical data, protein restriction, metabolic decompensation). When possible, median and interquartile range (IQR, i.e. 25–75%) are calculated.
inuline clearance technique, and expressed as mL/min/1.73 m2. Renal dysfunction was defined as GFR < 90 mL/min/1.73 m2.
Results Twelve patients (6 boys, 7 from BCH) born between 1984 and 2005 underwent 17 LTs, with a median follow-up of 17 years. PA was diagnosed in the first month of life (median 5 days, IQR: 3–20 days), with symptoms of intoxication such as coma, hypotonia, ketoacidosis and hyperammonemia, or after targeted screening where a previous sibling was affected for P5 and P9. Medical management included a strict low-protein diet (0.6–1.2 g/ kg/day) and L-Carnitine supplementation. Antibiotics, biotin supplementation and sodium benzoate were used in individual cases. Seven patients required nasogastric or gastrostomy tube feeding in order to achieve optimal caloric intake and reduce night catabolism. Before LT, all patients had a normal height and weight for their age. Four patients had severe osteopenia (P2, P10, P11, P12) evaluated by radiological criteria (P2, P11) or absorptiometry (P10: Z-score 2.6; P12: Z-score 5.8) with multiple fractures (P11, P12). Before LT, the median number of metabolic decompensations was six episodes per year per patient (IQR: 4.5–7) (Table 1). Median levels of propionate metabolites was 9 mM/mM of creatinine for the 3-hydroxypropionate, and 222 mM/mM of creatinine for the methylcitrate (P8, P9, P11; results 6 months before LT). All patients underwent heart ultrasonography during their pre-LT evaluation. Three patients displayed cardiomyopathy and were further evaluated with a cardiac catheterization: blood pressure values were normal in all three patients, and the clamping test of the inferior vena cava was normal except for P10. None of the patients had pulmonary symptoms. The renal function was assessed before LT in eight patients, with a median GFR of 86 mL/min/1.73 m2 (IQR: 77.5–104).
The accumulation of specific propionate metabolites in urine (3-hydroxypropionate, propionyl glycine, tiglylglycine and methylcitrate) was measured by gas chromatography–mass spectrometry at NCK, before and after LT. At BCH, organic acid analysis was undertaken using a semi-quantitative method that was in use at that time.
LT was performed between 1991 and 2013. The indications were frequent metabolic decompensations (eight patients), cardiomyopathy (three patients), pre-emptive treatment (two patients), and cirrhosis (one patient). Four patients required a retransplantation: two for biliary cirrhosis secondary to hepatic artery thrombosis (HAT, P6: delay 5 years and 4 months for each retransplantation; P10: delay 4 years), one for primary nonfunction of the graft (P1: delay 3 days), one for hepatic dysfunction after HAT (P8: delay 7 days). The median age at first transplantation was 3.2 years (range IQR: 1.6–6.8 years) (Table 1).
GFR was either estimated (eGFR) using the plasma creatinine levels and the Schwartz formula (12), or measured (mGFR) via radionuclide, iohexol or
All patients received a graft from a deceased donor. Twelve out of 17 LT were performed with a reduced graft (Table 1).
Acute metabolic decompensations are defined as ketoacidosis requiring emergency treatment and hospitalization. The diagnosis of hypokinetic dilated cardiomyopathy was made by echocardiography (dilated cardiac muscle, thin walls, ejection fraction
