YMGME-05748; No. of pages: 4; 4C: Molecular Genetics and Metabolism xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Conference Proceedings
Dietary protein in urea cycle defects: How much? Which? How?☆ Avihu Boneh ⁎ Murdoch Childrens Research Institute, Victorian Clinical Genetics Services, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, Australia Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
a r t i c l e
i n f o
Available online xxxx Keywords: Urea cycle Catabolism Energy Low protein diet Recommended daily intake
a b s t r a c t Dietary recommendations for patients with urea cycle disorders (UCDs) are designed to prevent metabolic decompensation (primarily hyperammonaemia), and to enable normal growth. They are based on the ‘recommended daily intake’ guidelines, on theoretical considerations and on local experience. A retrospective dietary review of 28 patients with UCDs in good metabolic control, at different ages, indicates that most patients can tolerate a natural protein intake that is compatible with metabolic stability and good growth. However, protein aversion presents a problem in many patients, leading to poor compliance with the prescribed daily protein intake. These patients are at risk of chronic protein deficiency. Failing to recognise this risk, and further restricting protein intake because of persistent hyperammonaemia may aggravate the deficiency and potentially lead to episodes of metabolic decompensation for which no clear cause is found. These patients may need on-going supplementation with essential amino acids (EAA) to prevent protein malnutrition. Current recommendations for the management of acute metabolic decompensation include cessation of protein intake whilst increasing energy (calorie) intake in the first 24 h. We have found that plasma concentrations of all EAA are low at the time of admission to hospital for metabolic decompensation, with correlation between low EAA concentrations, particularly branched-chain amino acids, and hyperammonaemia. Thus, supplementation with EAA should be considered at times of metabolic decompensation. Finally, it would be advantageous to treat patients in metabolic decompensation through enteral supplementation, whenever possible, because of the contribution of the splanchnic (portal-drained viscera) system to protein retention and metabolism.
1. Introduction The primary goal of the dietary therapy of patients with urea cycle disorders (UCDs) is to maintain good metabolic control whilst enabling normal growth and development. Since CNS toxicity in UCDs is directly related to tissue concentrations of ammonia [1,2], and thus to nitrogen load, these goals have been translated in various guidelines into: “Avoid too much protein”, and “Provide sufficient protein for growth” [3–6]. It is recognised that during times of illness there is (a risk of) catabolism and therefore, it has long been recommended that treatment should consist of: “Avoid/reverse catabolism: provide sufficient calories” and “Assume catabolism: stop protein intake” [3–6]. However, treatment recommendations in IEM in general and, more specifically, in UCDs are based on theoretical considerations and on a considerable number of assumptions, on personal experience, on small or large cohort retrospective studies and very rarely on double-blind, comparative-controlled
☆ Presented at the 4th International Symposium on Urea Cycle Disorders, Barcelona, 2013. ⁎ Metabolic Genetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, VIC 3052, Australia. Fax: +61 3 8341 6390.
studies. Moreover, local practices may change based on availability of foods, cultural habits and diets etc. Within the scope of the UCD treatment guidelines, there remain several questions regarding the total daily protein and energy requirements of patients with UCDs for good metabolic control and adequate growth, the amount of natural protein that these patients tolerate, protein intake and reversal of catabolism at times of hyperammonaemia and the optimal mode of providing protein to these patients at times of metabolic decompensation. The purpose of this review is to address some of these questions. 2. What do we need to know when designing a diet for patients with UCDs? The current inherent assumption in designing an age appropriate diet is that energy (calorie) requirement is the drive for food intake, whereas protein requirement does not drive food intake [7]. In order to prescribe an age-appropriate diet for a patient with UCD we need to know the patient's energy requirements (which are dependent on the patient's age, gender and physical activity), their protein requirements for metabolic stability and for growth, and, ideally, measurements of the capacity of protein metabolism and tolerance when the
http://dx.doi.org/10.1016/j.ymgme.2014.04.009 1096-7192/
Please cite this article as: A. Boneh, Dietary protein in urea cycle defects: How much? Which? How?, Mol. Genet. Metab. (2014), http://dx.doi.org/ 10.1016/j.ymgme.2014.04.009
2
A. Boneh / Molecular Genetics and Metabolism xxx (2014) xxx–xxx
patient is ‘well’ and acutely when ‘unwell’. It is assumed (but not proven) that children with UCDs do not differ from their healthy peers in their essential dietary requirements. Thus, the basis of the ageappropriate dietary recommendations in the treatment of patients with UCDs has been the Recommended Daily Intake (RDI) for energy and protein, which is a population-based mean intake (of energy, or protein, or nutrient intake) +2 SD of the mean (i.e. 95% percentile for nutrient intake). It follows that about 45–50% of patients can do with less daily protein intake and would still consume the mean protein intake of the respective population. Alternatively, a fractional calculation of dietary requirements can be made, which takes into account the basal metabolic rate + growth + activity + other factors. However, there are disturbing differences between different studies (and authors). For example, the WHO technical report on protein intake, published in 2007, differs from the same report published in 1985 [7]. Regardless of the method used for assessing energy needs, in prescribing a diet for patients with UCDs it is often recommended that energy intake be increased by a ‘factor’ to prevent catabolism and improve metabolic control during illness and during activity, usually through increased fat and carbohydrate intake. The basis for the dietary recommendations of protein intake in patients with UCDs is: “Protein and amino acid requirements in human nutrition: Report of a joint FAO/WHO/UNU expert consultation (WHO technical report series; no. 935), 2007” [7] (cited in the recent suggested guidelines for the treatment of UCDs) [6]. The recommended daily protein intake in this report is considerably low. However, the authors of the report acknowledge that nitrogen balance does not necessarily reflect optimal protein intake and that “the safe population intake will approximate to a value which is somewhat greater than the requirement + 1.96 SD of intake” (Section 14.1.1; page 241). Thus, a correction for protein digestibility and amino acid score value needs to be made (Section 14.1.5; page 242). In practice, natural protein intake is usually individualised and, in some metabolic centres, may be ‘pushed to maximum tolerance’. In other centres the prescribed intake of natural protein is limited and amino acid formulae are used to substitute for natural protein intake. This has been translated in some guidelines into: “provide 0.8 g natural protein/kg/day + essential amino acid formula” [8].
3. What is the natural protein tolerance of patients with UCDs? We recently analysed the daily amount of protein (in g/kg body weight) consumed by 28 paediatric patients with UCDs (up to 18 years of age) at different ages, all in good metabolic control, as recalled and recorded in the outpatient clinics over time (Fig. 1) (Kuypers et al., unpublished observations). Although these data may not be compatible with stringent scientific criteria, they are practical, given that on-going treatment decisions are based on information obtained in follow-up clinic reviews. There were 16 female- and 12 male-patients with various UCDs: 17 had ornithine transcarbamylase (OTC) deficiency; three had citrullinaemia type I (Cit I); five had carbamyl-phosphate synthetase I (CPS I) deficiency; and three had argininosuccinic-aciduria (ASA). All patients were treated with sodium benzoate (but not with phenylbutyrate, phenylacetate or Ammunol) and citrulline or arginine. Most patients consume between 1 and 1.8 g natural protein/kg body weight per day and some (mainly male patients with late onset OTC deficiency) tolerate larger amounts of natural protein/kg/day. Thus, at most times, patients with UCDs may tolerate natural protein intake well within the ageappropriate recommendation, whilst maintaining good metabolic control. However, some patients, or patients at particular times, consume less than the optimal daily protein intake. These patients warrant special attention. 4. Specific dietary issues of patients with UCDs Food refusal and protein aversion have long been recognised in patients with UCDs. Food refusal in these patients could be the result of protein aversion, alterations in serotonin and other neurotransmitters affecting satiety and nausea post high protein ingestion due to high ammonia levels [9]. In a ‘real time observational study’ we collected dietary data of patients with UCDs treated at our centre during 2007 (Fig. 2) (Watkins et al., unpublished observations). There were 17 patients (10 male patients, 7 female patients) aged 11 months–56 years. Nine patients had OTC deficiency, four had CPS I deficiency, three had ASA and one had Cit I (these patients were also included in the study mentioned
Fig. 1. Natural protein intake of patients with UCDs. Data were collected during clinic reviews (by and large), through phone communication and through 3-day food diaries. OTC: ornithine transcarbamylase (F—female; M—male); Cit I: citrullinaemia type I; CPS I: carbamyl-phosphate synthetase I deficiency; ASA: arginine-succinic aciduria. The symbols represent different urea cycle diseases (legend). The solid line represents the age-related recommended daily protein intake. Note: Protein intake N2.5 g/kg/day was noted consistently in 2 male patients with ‘attenuated’ OTC deficiency, and sporadically in one patient with ASA and one with Cit I.
Please cite this article as: A. Boneh, Dietary protein in urea cycle defects: How much? Which? How?, Mol. Genet. Metab. (2014), http://dx.doi.org/ 10.1016/j.ymgme.2014.04.009
A. Boneh / Molecular Genetics and Metabolism xxx (2014) xxx–xxx 18 16 14 12 10 8
No
6
Yes
4 2 0 Avoids food
Avoids high protein foods
Consumes less protein than prescribed
Consumes less calories than prescribed
Fig. 2. Dietary habits of patients with UCDs treated at our centre during 2007. Data were collected during the year in clinic reviews (“recall”).
above). Food refusal was noted in 15/17; avoidance of high protein foods in 13/17; lower protein intake than prescribed in 10/17; and lower energy intake than prescribed in 6/17. This small study led to a larger study in which the clinical, dietary and laboratory records of all patients with a confirmed diagnosis of UCD attending the metabolic clinic between 1972 and 2010 (n = 90) were reviewed [10]. Overall, approximately half of the patients displayed protein aversion, poor appetite, food refusal, poor variety of foods and frequent vomiting [10]. These results indicate that the daily protein intake of a large proportion of patients with UCDs may be borderline low or even inadequate and that careful monitoring of actual intake, as opposed to prescribed intake, is required in managing these patients. In summary: when monitoring protein intake of patients with UCDs one should consider that most patients with UCDs have protein aversion and are less likely to consume too much protein. Despite the capacity for natural protein tolerance within the safe range, patients may in fact not consume the prescribed daily protein. These patients are therefore at risk of being chronically protein-deficient. Pharmacological treatment with some nitrogen scavengers may aggravate essential amino acid (EAA) deficiency [11,12]. Therefore, one should regularly pay attention and monitor actual daily protein and energy intake, and their distribution throughout the day. Some patients may need EAA supplementation; the amount is variable and may change with age. It should be remembered that amino acids are not protein. Given that the quality of the protein consumed is taken into account in the dietary protein recommendations, it is possible that amino acids cannot be considered as a protein equivalent in a 1:1 ratio, and larger quantities of amino acid formulae will need to be consumed to bridge the gap in protein deficiency. Further study should be done to elucidate the protein-value of these formulae, their bio-availability and their age-appropriateness. 5. Acute decompensation treatment guidelines The inherent assumption dictating the approach to the management of a patient with UCD at times of decompensation and hyperammonaemia is that the patient is in a state of catabolism, imminent or present. This has been translated in various guidelines into: ‘Provide 100–120% calorie RDI’. Another inherent assumption is that at the time of catabolism amino acids cannot be effectively used for protein biosynthesis and that their tissue availability may exceed their maximal oxidation rate. This has been translated in the guidelines to: ‘Cease protein intake (for no more than 24 h) and re-introduce protein gradually (e.g. 1/2 of daily intake; increasing gradually thereafter)’ [6,13]. We reviewed the plasma ammonia concentrations and amino acid profiles of all patients with a known UCD admitted to hospital due to metabolic decompensation between January 1982 and December 2010 (N290 admissions) and analysed the data from all acute admissions where blood samples for plasma amino acid profiles and ammonia concentrations were taken simultaneously or within 30 min of each
3
other (96 admissions, however many results were obtained during admissions of one single patient with OTC deficiency) [15]. The results indicated low-normal or low plasma concentration of most amino acids, particularly the EAA. All three branched chain amino acids (BCAA) were below the normal range in 35/96 (36.5%) of all samples and in 30/79 (38.0%) of samples from OTC deficient patients. Of the BCAA, valine concentration was most frequently low (in 57/96 (59.4%) of all samples and 51/79 (64.9%) of OTC deficient patients), and by the greatest margin when compared with its reference range. Of particular importance is the finding that there was a strong correlation between plasma concentrations of BCAA and that of other essential amino acids in the whole cohort, regardless of age. Indeed, in only 4/35 samples in which BCAA concentrations were low, were those of the other EAA (phenylalanine, tyrosine and threonine) within the normal range [15]. Thus, the assumption that tissue availability of amino acids may exceed their maximal oxidation rate could not be confirmed. It is likely that during intercurrent illnesses there is, in fact, EAA deficiency due to poor protein intake at these times. Low plasma concentrations of BCAA in patients with UCDs during metabolic decompensation and hyperammonaemia have been noted previously. Holecek et al. have shown that acute hyperammonaemia leads to activation of BCAA catabolism and to the reduction of their concentration in plasma [14]. An additional contributing factor is the use of the nitrogen scavengers phenylacetate or phenylbutyrate in the management of patients with UCDs, as these medications lead to BCAA depletion by depleting glutamine, as mentioned above [11,12]. Given the strong correlation between BCAA and other EAA depletions, our findings suggest that in addition to the abovementioned factors, acute protein deficiency (presumably because of poor intake or vomiting prior to metabolic decompensation) is a significant contributing factor leading to BCAA depletion [15]. This would be further aggravated if the patient is chronically borderline- or overtly-protein deficient. One could speculate that the reason for the metabolic decompensation in patients who present with hyperammonaemia without a clear clinical cause (e.g. infection) may be “acute on chronic” protein deficiency. This hypothesis needs to be prospectively tested. 6. How should we reverse catabolism? There is ample literature surrounding the optimal nutritional means to reverse catabolism in sick children and adults. For example, as early as 1985, Pollack et al. have provided evidence that not only energy deficiency but also protein deficiency contributes to physiologic instability of critically ill children and to extended length of stay in hospital [16]. Van den Akker et al. have shown that administration of amino acids to premature infants reversed the catabolic state that would otherwise occur when amino acids are withheld [17]. In a recent double-blind randomised controlled study on critically ill infants with acute bronchiolitis, de Betue et al. have shown that provision of protein (as well as energy) in the first days after admission, at quantities higher than those usually recommended, led to stimulated protein synthesis exceeding the rate of concomitant stimulated protein breakdown and, hence, to a positive protein balance. They concluded that increased protein and energy intakes should be prescribed to critically ill infants with viral bronchiolitis [18]. These reports suggest that protein supplementation should be considered in the nutritional management of patients with UCDs during acute metabolic decompensation. However, caution should be exercised in providing protein to patients with hyperammonaemia and this notion needs to be proven in prospective studies. The recent suggested guidelines for the management of patients with UCDs indicate that “The aim is to minimise protein (nitrogen) intake temporarily and prevent endogenous protein catabolism whilst providing enough energy to meet metabolic demands” [6]. Within this rationale, it would seem prudent to cease natural protein intake (for no more than 24 h), to provide 100–120% of the calorie RDI and to supplement with EAA (particularly BCAA) that will enhance
Please cite this article as: A. Boneh, Dietary protein in urea cycle defects: How much? Which? How?, Mol. Genet. Metab. (2014), http://dx.doi.org/ 10.1016/j.ymgme.2014.04.009
4
A. Boneh / Molecular Genetics and Metabolism xxx (2014) xxx–xxx
anabolism but will not lead to excessive nitrogen load (we have been using, empirically, 0.5 g protein equivalent EAA/kg/day). Thereafter, protein should be re-introduced at 1/2 of daily intake, increasing gradually as per the guidelines and the clinical state of the patient. This is supported by a study by Rennie et al., who have shown that BCAA act as fuels and anabolic signals in human muscle, through activation of signalling pathways, regardless of insulin availability [19]. 7. How should protein be provided to patients? There is ample evidence that enteral protein intake is advantageous over par-enteral protein intake in promoting anabolism, thus supporting the recent suggested guidelines for the management of patients with UCDs [6] (see also [3,4]). The portal-drained viscera (stomach, intestines, pancreas, and spleen), in which the acute anabolic effect of a mixed meal occurs primarily, represent 4 to 6% of body weight, but account for up to 35% of whole-body protein turnover and energy expenditure (summarised in [20]). Studies in piglets show that “First pass extraction” of dietary amino acids occurs in the portal-drained viscera, leading to protein synthesis, other (non-essential) amino acid synthesis, and oxidation or transport into the portal vein [20]. This is followed by “first pass extraction” in the liver, leading to further protein and peptide synthesis and oxidation and transport into the general circulation and peripheral organs (reviewed in [20]). From a practical perspective, establishing IV access may take time in a sick, dehydrated patient, a period of time that may be precious and may be used to provide the patient with calories and nutrients. Provision of enteral feeds enables the concomitant use of an IV line for medications. Moreover, it should be remembered that it is possible to provide more calories and nutrients in a smaller volume through enteral feeds than via par-enteral nutrition. This may be particularly important when concern regarding intracranial pressure is raised and fluid volume restriction is required. Taken together, these considerations can be translated into a guideline: “If the gut is functional, use it!” We have provided enteral nutrition to patients during times of haemofiltration, once their haemodynamic state has been stabilised, with no ill effects. 8. Future perspectives Treatment recommendations for UCDs based on large scale double blind controlled studies are unlikely to be at hand because of the rarity of the disorders and the diverse treatment practices in different centres. Yet, there is a wide scope for research into a more evidence-based approach to the dietary management of patients with UCDs in large observational and comparative studies. Some of the questions that should be studied include: • Can we enhance the use of natural protein containing foods based on their respective amino acid composition and their suitability for specific UCDs? • What is the role of EAAs in the acute management of a patient with hyperammonaemia? • Can we quantify the anabolic effect of enteral vs. par-enteral nutrition in IEM? What are the limitations – if any – of using the gut for managing acute decompensation in UCDs? • Do we need to look at protein to energy ratio rather than at daily protein and energy requirements separately? What is a safe protein to energy ratio in UCDs?
These questions can be answered only through large collaborative studies, incorporating and comparing detailed records of management, compliance and outcome. Acknowledgments I wish to acknowledge the dedicated work of the dietitians Dorothy Francis, Maureen Humphrey, Judy Nation, Jamie Errico and Jemma Watkins and the students Tatijana Gardeitchick, Simon Rodney and Julia Kuypers. This work was supported by the Victorian Government's Operational Infrastructure Support Program. References [1] O. Braissant, Current concepts in the pathogenesis of urea cycle disorders, Mol. Genet. Metab. 100 (2010) S3–S12. [2] O. Braissant, Ammonia toxicity to the brain: effects on creatine metabolism and transport and protective roles of creatine, Mol. Genet. Metab. 100 (Suppl. 1) (2010) S53–S58. [3] J.V. Leonard, The nutritional management of urea cycle disorders, J. Pediatr. 138 (2001) S40–44 (discussion S44-45). [4] M. Summar, Current strategies for the management of neonatal urea cycle disorders, J. Pediatr. 138 (2001) S30–S39. [5] M. Summar, M. Tuchman, Proceedings of a consensus conference for the management of patients with urea cycle disorders, J. Pediatr. 138 (2001) S6–S10. [6] J. Haberle, N. Boddaert, A. Burlina, A. Chakrapani, M. Dixon, M. Huemer, D. Karall, D. Martinelli, P.S. Crespo, R. Santer, A. Servais, V. Valayannopoulos, M. Lindner, V. Rubio, C. Dionisi-Vici, Suggested guidelines for the diagnosis and management of urea cycle disorders, Orphanet. J. Rare Dis. 7 (2012) 32. [7] W.H.O.F.A.O.U.N.U.E.C., Joint, Protein and amino acid requirements in human nutrition, World Health Organization Technical Report Series, 2007, pp. 1–265, (back cover). [8] S. Adam, M.F. Almeida, M. Assoun, J. Baruteau, S.M. Bernabei, S. Bigot, H. Champion, A. Daly, M. Dassy, S. Dawson, M. Dixon, K. Dokoupil, S. Dubois, C. Dunlop, S. Evans, F. Eyskens, A. Faria, E. Favre, C. Ferguson, C. Goncalves, J. Gribben, M. Heddrich-Ellerbrok, C. Jankowski, R. Janssen-Regelink, C. Jouault, C. Laguerre, S. Le Verge, R. Link, S. Lowry, K. Luyten, A. Macdonald, C. Maritz, S. McDowell, U. Meyer, A. Micciche, M. Robert, L.V. Robertson, J.C. Rocha, C. Rohde, I. Saruggia, E. Sjoqvist, J. Stafford, A. Terry, R. Thom, K. Vande Kerckhove, M. van Rijn, A. van Teeffelen-Heithoff, A.V. Wegberg, K. van Wyk, C. Vasconcelos, H. Vestergaard, D. Webster, F.J. White, J. Wildgoose, H. Zweers, Dietary management of urea cycle disorders: European practice, Mol. Genet. Metab. 110 (2013) 439–445. [9] S.L. Hyman, J.T. Coyle, J.C. Parke, C. Porter, G.H. Thomas, W. Jankel, M.L. Batshaw, Anorexia and altered serotonin metabolism in a patient with argininosuccinic aciduria, J. Pediatr. 108 (1986) 705–709. [10] T. Gardeitchik, M. Humphrey, J. Nation, A. Boneh, Early clinical manifestations and eating patterns in patients with urea cycle disorders, J. Pediatr. 161 (2012) 328–332. [11] F. Scaglia, S. Carter, W.E. O'Brien, B. Lee, Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients, Mol. Genet. Metab. 81 (2004) S79–S85. [12] F. Scaglia, New insights in nutritional management and amino acid supplementation in urea cycle disorders, Mol. Genet. Metab. 100 (2010) S72–S76. [13] R.H. Singh, Nutritional management of patients with urea cycle disorders, J. Inherit. Metab. Dis. 30 (2007) 880–887. [14] M. Holecek, R. Kandar, L. Sispera, M. Kovarik, Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle, Amino Acids 40 (2011) 575–584. [15] S. Rodney, A. Boneh, Amino acid profiles in patients with urea cycle disorders at admission to hospital due to metabolic decompensation, JIMD Rep. 9 (2013) 97–104. [16] M.M. Pollack, U.E. Ruttimann, J.S. Wiley, Nutritional depletions in critically ill children: associations with physiologic instability and increased quantity of care JPEN, J. Parenter. Enter. Nutr. 9 (1985) 309–313. [17] C.H. van den Akker, F.W. te Braake, D.J. Wattimena, G. Voortman, H. Schierbeek, A. Vermes, J.B. van Goudoever, Effects of early amino acid administration on leucine and glucose kinetics in premature infants, Pediatr. Res. 59 (2006) 732–735. [18] C.T. de Betue, D.A. van Waardenburg, N.E. Deutz, H.M. van Eijk, J.B. van Goudoever, Y.C. Luiking, L.J. Zimmermann, K.F. Joosten, Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial, Arch. Dis. Child. 96 (2011) 817–822. [19] M.J. Rennie, J. Bohe, K. Smith, H. Wackerhage, P. Greenhaff, Branched-chain amino acids as fuels and anabolic signals in human muscle, J. Nutr. 136 (2006) 264S–268S. [20] B. Stoll, D.G. Burrin, Measuring splanchnic amino acid metabolism in vivo using stable isotopic tracers, J. Anim. Sci. 84 (2006) E60–E72 (Suppl.).
Please cite this article as: A. Boneh, Dietary protein in urea cycle defects: How much? Which? How?, Mol. Genet. Metab. (2014), http://dx.doi.org/ 10.1016/j.ymgme.2014.04.009
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Conference Proceedings
Dietary protein in urea cycle defects: How much? Which? How?☆ Avihu Boneh ⁎ Murdoch Childrens Research Institute, Victorian Clinical Genetics Services, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, Australia Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
a r t i c l e
i n f o
Available online xxxx Keywords: Urea cycle Catabolism Energy Low protein diet Recommended daily intake
a b s t r a c t Dietary recommendations for patients with urea cycle disorders (UCDs) are designed to prevent metabolic decompensation (primarily hyperammonaemia), and to enable normal growth. They are based on the ‘recommended daily intake’ guidelines, on theoretical considerations and on local experience. A retrospective dietary review of 28 patients with UCDs in good metabolic control, at different ages, indicates that most patients can tolerate a natural protein intake that is compatible with metabolic stability and good growth. However, protein aversion presents a problem in many patients, leading to poor compliance with the prescribed daily protein intake. These patients are at risk of chronic protein deficiency. Failing to recognise this risk, and further restricting protein intake because of persistent hyperammonaemia may aggravate the deficiency and potentially lead to episodes of metabolic decompensation for which no clear cause is found. These patients may need on-going supplementation with essential amino acids (EAA) to prevent protein malnutrition. Current recommendations for the management of acute metabolic decompensation include cessation of protein intake whilst increasing energy (calorie) intake in the first 24 h. We have found that plasma concentrations of all EAA are low at the time of admission to hospital for metabolic decompensation, with correlation between low EAA concentrations, particularly branched-chain amino acids, and hyperammonaemia. Thus, supplementation with EAA should be considered at times of metabolic decompensation. Finally, it would be advantageous to treat patients in metabolic decompensation through enteral supplementation, whenever possible, because of the contribution of the splanchnic (portal-drained viscera) system to protein retention and metabolism.
1. Introduction The primary goal of the dietary therapy of patients with urea cycle disorders (UCDs) is to maintain good metabolic control whilst enabling normal growth and development. Since CNS toxicity in UCDs is directly related to tissue concentrations of ammonia [1,2], and thus to nitrogen load, these goals have been translated in various guidelines into: “Avoid too much protein”, and “Provide sufficient protein for growth” [3–6]. It is recognised that during times of illness there is (a risk of) catabolism and therefore, it has long been recommended that treatment should consist of: “Avoid/reverse catabolism: provide sufficient calories” and “Assume catabolism: stop protein intake” [3–6]. However, treatment recommendations in IEM in general and, more specifically, in UCDs are based on theoretical considerations and on a considerable number of assumptions, on personal experience, on small or large cohort retrospective studies and very rarely on double-blind, comparative-controlled
☆ Presented at the 4th International Symposium on Urea Cycle Disorders, Barcelona, 2013. ⁎ Metabolic Genetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, VIC 3052, Australia. Fax: +61 3 8341 6390.
studies. Moreover, local practices may change based on availability of foods, cultural habits and diets etc. Within the scope of the UCD treatment guidelines, there remain several questions regarding the total daily protein and energy requirements of patients with UCDs for good metabolic control and adequate growth, the amount of natural protein that these patients tolerate, protein intake and reversal of catabolism at times of hyperammonaemia and the optimal mode of providing protein to these patients at times of metabolic decompensation. The purpose of this review is to address some of these questions. 2. What do we need to know when designing a diet for patients with UCDs? The current inherent assumption in designing an age appropriate diet is that energy (calorie) requirement is the drive for food intake, whereas protein requirement does not drive food intake [7]. In order to prescribe an age-appropriate diet for a patient with UCD we need to know the patient's energy requirements (which are dependent on the patient's age, gender and physical activity), their protein requirements for metabolic stability and for growth, and, ideally, measurements of the capacity of protein metabolism and tolerance when the
http://dx.doi.org/10.1016/j.ymgme.2014.04.009 1096-7192/
Please cite this article as: A. Boneh, Dietary protein in urea cycle defects: How much? Which? How?, Mol. Genet. Metab. (2014), http://dx.doi.org/ 10.1016/j.ymgme.2014.04.009
2
A. Boneh / Molecular Genetics and Metabolism xxx (2014) xxx–xxx
patient is ‘well’ and acutely when ‘unwell’. It is assumed (but not proven) that children with UCDs do not differ from their healthy peers in their essential dietary requirements. Thus, the basis of the ageappropriate dietary recommendations in the treatment of patients with UCDs has been the Recommended Daily Intake (RDI) for energy and protein, which is a population-based mean intake (of energy, or protein, or nutrient intake) +2 SD of the mean (i.e. 95% percentile for nutrient intake). It follows that about 45–50% of patients can do with less daily protein intake and would still consume the mean protein intake of the respective population. Alternatively, a fractional calculation of dietary requirements can be made, which takes into account the basal metabolic rate + growth + activity + other factors. However, there are disturbing differences between different studies (and authors). For example, the WHO technical report on protein intake, published in 2007, differs from the same report published in 1985 [7]. Regardless of the method used for assessing energy needs, in prescribing a diet for patients with UCDs it is often recommended that energy intake be increased by a ‘factor’ to prevent catabolism and improve metabolic control during illness and during activity, usually through increased fat and carbohydrate intake. The basis for the dietary recommendations of protein intake in patients with UCDs is: “Protein and amino acid requirements in human nutrition: Report of a joint FAO/WHO/UNU expert consultation (WHO technical report series; no. 935), 2007” [7] (cited in the recent suggested guidelines for the treatment of UCDs) [6]. The recommended daily protein intake in this report is considerably low. However, the authors of the report acknowledge that nitrogen balance does not necessarily reflect optimal protein intake and that “the safe population intake will approximate to a value which is somewhat greater than the requirement + 1.96 SD of intake” (Section 14.1.1; page 241). Thus, a correction for protein digestibility and amino acid score value needs to be made (Section 14.1.5; page 242). In practice, natural protein intake is usually individualised and, in some metabolic centres, may be ‘pushed to maximum tolerance’. In other centres the prescribed intake of natural protein is limited and amino acid formulae are used to substitute for natural protein intake. This has been translated in some guidelines into: “provide 0.8 g natural protein/kg/day + essential amino acid formula” [8].
3. What is the natural protein tolerance of patients with UCDs? We recently analysed the daily amount of protein (in g/kg body weight) consumed by 28 paediatric patients with UCDs (up to 18 years of age) at different ages, all in good metabolic control, as recalled and recorded in the outpatient clinics over time (Fig. 1) (Kuypers et al., unpublished observations). Although these data may not be compatible with stringent scientific criteria, they are practical, given that on-going treatment decisions are based on information obtained in follow-up clinic reviews. There were 16 female- and 12 male-patients with various UCDs: 17 had ornithine transcarbamylase (OTC) deficiency; three had citrullinaemia type I (Cit I); five had carbamyl-phosphate synthetase I (CPS I) deficiency; and three had argininosuccinic-aciduria (ASA). All patients were treated with sodium benzoate (but not with phenylbutyrate, phenylacetate or Ammunol) and citrulline or arginine. Most patients consume between 1 and 1.8 g natural protein/kg body weight per day and some (mainly male patients with late onset OTC deficiency) tolerate larger amounts of natural protein/kg/day. Thus, at most times, patients with UCDs may tolerate natural protein intake well within the ageappropriate recommendation, whilst maintaining good metabolic control. However, some patients, or patients at particular times, consume less than the optimal daily protein intake. These patients warrant special attention. 4. Specific dietary issues of patients with UCDs Food refusal and protein aversion have long been recognised in patients with UCDs. Food refusal in these patients could be the result of protein aversion, alterations in serotonin and other neurotransmitters affecting satiety and nausea post high protein ingestion due to high ammonia levels [9]. In a ‘real time observational study’ we collected dietary data of patients with UCDs treated at our centre during 2007 (Fig. 2) (Watkins et al., unpublished observations). There were 17 patients (10 male patients, 7 female patients) aged 11 months–56 years. Nine patients had OTC deficiency, four had CPS I deficiency, three had ASA and one had Cit I (these patients were also included in the study mentioned
Fig. 1. Natural protein intake of patients with UCDs. Data were collected during clinic reviews (by and large), through phone communication and through 3-day food diaries. OTC: ornithine transcarbamylase (F—female; M—male); Cit I: citrullinaemia type I; CPS I: carbamyl-phosphate synthetase I deficiency; ASA: arginine-succinic aciduria. The symbols represent different urea cycle diseases (legend). The solid line represents the age-related recommended daily protein intake. Note: Protein intake N2.5 g/kg/day was noted consistently in 2 male patients with ‘attenuated’ OTC deficiency, and sporadically in one patient with ASA and one with Cit I.
Please cite this article as: A. Boneh, Dietary protein in urea cycle defects: How much? Which? How?, Mol. Genet. Metab. (2014), http://dx.doi.org/ 10.1016/j.ymgme.2014.04.009
A. Boneh / Molecular Genetics and Metabolism xxx (2014) xxx–xxx 18 16 14 12 10 8
No
6
Yes
4 2 0 Avoids food
Avoids high protein foods
Consumes less protein than prescribed
Consumes less calories than prescribed
Fig. 2. Dietary habits of patients with UCDs treated at our centre during 2007. Data were collected during the year in clinic reviews (“recall”).
above). Food refusal was noted in 15/17; avoidance of high protein foods in 13/17; lower protein intake than prescribed in 10/17; and lower energy intake than prescribed in 6/17. This small study led to a larger study in which the clinical, dietary and laboratory records of all patients with a confirmed diagnosis of UCD attending the metabolic clinic between 1972 and 2010 (n = 90) were reviewed [10]. Overall, approximately half of the patients displayed protein aversion, poor appetite, food refusal, poor variety of foods and frequent vomiting [10]. These results indicate that the daily protein intake of a large proportion of patients with UCDs may be borderline low or even inadequate and that careful monitoring of actual intake, as opposed to prescribed intake, is required in managing these patients. In summary: when monitoring protein intake of patients with UCDs one should consider that most patients with UCDs have protein aversion and are less likely to consume too much protein. Despite the capacity for natural protein tolerance within the safe range, patients may in fact not consume the prescribed daily protein. These patients are therefore at risk of being chronically protein-deficient. Pharmacological treatment with some nitrogen scavengers may aggravate essential amino acid (EAA) deficiency [11,12]. Therefore, one should regularly pay attention and monitor actual daily protein and energy intake, and their distribution throughout the day. Some patients may need EAA supplementation; the amount is variable and may change with age. It should be remembered that amino acids are not protein. Given that the quality of the protein consumed is taken into account in the dietary protein recommendations, it is possible that amino acids cannot be considered as a protein equivalent in a 1:1 ratio, and larger quantities of amino acid formulae will need to be consumed to bridge the gap in protein deficiency. Further study should be done to elucidate the protein-value of these formulae, their bio-availability and their age-appropriateness. 5. Acute decompensation treatment guidelines The inherent assumption dictating the approach to the management of a patient with UCD at times of decompensation and hyperammonaemia is that the patient is in a state of catabolism, imminent or present. This has been translated in various guidelines into: ‘Provide 100–120% calorie RDI’. Another inherent assumption is that at the time of catabolism amino acids cannot be effectively used for protein biosynthesis and that their tissue availability may exceed their maximal oxidation rate. This has been translated in the guidelines to: ‘Cease protein intake (for no more than 24 h) and re-introduce protein gradually (e.g. 1/2 of daily intake; increasing gradually thereafter)’ [6,13]. We reviewed the plasma ammonia concentrations and amino acid profiles of all patients with a known UCD admitted to hospital due to metabolic decompensation between January 1982 and December 2010 (N290 admissions) and analysed the data from all acute admissions where blood samples for plasma amino acid profiles and ammonia concentrations were taken simultaneously or within 30 min of each
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other (96 admissions, however many results were obtained during admissions of one single patient with OTC deficiency) [15]. The results indicated low-normal or low plasma concentration of most amino acids, particularly the EAA. All three branched chain amino acids (BCAA) were below the normal range in 35/96 (36.5%) of all samples and in 30/79 (38.0%) of samples from OTC deficient patients. Of the BCAA, valine concentration was most frequently low (in 57/96 (59.4%) of all samples and 51/79 (64.9%) of OTC deficient patients), and by the greatest margin when compared with its reference range. Of particular importance is the finding that there was a strong correlation between plasma concentrations of BCAA and that of other essential amino acids in the whole cohort, regardless of age. Indeed, in only 4/35 samples in which BCAA concentrations were low, were those of the other EAA (phenylalanine, tyrosine and threonine) within the normal range [15]. Thus, the assumption that tissue availability of amino acids may exceed their maximal oxidation rate could not be confirmed. It is likely that during intercurrent illnesses there is, in fact, EAA deficiency due to poor protein intake at these times. Low plasma concentrations of BCAA in patients with UCDs during metabolic decompensation and hyperammonaemia have been noted previously. Holecek et al. have shown that acute hyperammonaemia leads to activation of BCAA catabolism and to the reduction of their concentration in plasma [14]. An additional contributing factor is the use of the nitrogen scavengers phenylacetate or phenylbutyrate in the management of patients with UCDs, as these medications lead to BCAA depletion by depleting glutamine, as mentioned above [11,12]. Given the strong correlation between BCAA and other EAA depletions, our findings suggest that in addition to the abovementioned factors, acute protein deficiency (presumably because of poor intake or vomiting prior to metabolic decompensation) is a significant contributing factor leading to BCAA depletion [15]. This would be further aggravated if the patient is chronically borderline- or overtly-protein deficient. One could speculate that the reason for the metabolic decompensation in patients who present with hyperammonaemia without a clear clinical cause (e.g. infection) may be “acute on chronic” protein deficiency. This hypothesis needs to be prospectively tested. 6. How should we reverse catabolism? There is ample literature surrounding the optimal nutritional means to reverse catabolism in sick children and adults. For example, as early as 1985, Pollack et al. have provided evidence that not only energy deficiency but also protein deficiency contributes to physiologic instability of critically ill children and to extended length of stay in hospital [16]. Van den Akker et al. have shown that administration of amino acids to premature infants reversed the catabolic state that would otherwise occur when amino acids are withheld [17]. In a recent double-blind randomised controlled study on critically ill infants with acute bronchiolitis, de Betue et al. have shown that provision of protein (as well as energy) in the first days after admission, at quantities higher than those usually recommended, led to stimulated protein synthesis exceeding the rate of concomitant stimulated protein breakdown and, hence, to a positive protein balance. They concluded that increased protein and energy intakes should be prescribed to critically ill infants with viral bronchiolitis [18]. These reports suggest that protein supplementation should be considered in the nutritional management of patients with UCDs during acute metabolic decompensation. However, caution should be exercised in providing protein to patients with hyperammonaemia and this notion needs to be proven in prospective studies. The recent suggested guidelines for the management of patients with UCDs indicate that “The aim is to minimise protein (nitrogen) intake temporarily and prevent endogenous protein catabolism whilst providing enough energy to meet metabolic demands” [6]. Within this rationale, it would seem prudent to cease natural protein intake (for no more than 24 h), to provide 100–120% of the calorie RDI and to supplement with EAA (particularly BCAA) that will enhance
Please cite this article as: A. Boneh, Dietary protein in urea cycle defects: How much? Which? How?, Mol. Genet. Metab. (2014), http://dx.doi.org/ 10.1016/j.ymgme.2014.04.009
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anabolism but will not lead to excessive nitrogen load (we have been using, empirically, 0.5 g protein equivalent EAA/kg/day). Thereafter, protein should be re-introduced at 1/2 of daily intake, increasing gradually as per the guidelines and the clinical state of the patient. This is supported by a study by Rennie et al., who have shown that BCAA act as fuels and anabolic signals in human muscle, through activation of signalling pathways, regardless of insulin availability [19]. 7. How should protein be provided to patients? There is ample evidence that enteral protein intake is advantageous over par-enteral protein intake in promoting anabolism, thus supporting the recent suggested guidelines for the management of patients with UCDs [6] (see also [3,4]). The portal-drained viscera (stomach, intestines, pancreas, and spleen), in which the acute anabolic effect of a mixed meal occurs primarily, represent 4 to 6% of body weight, but account for up to 35% of whole-body protein turnover and energy expenditure (summarised in [20]). Studies in piglets show that “First pass extraction” of dietary amino acids occurs in the portal-drained viscera, leading to protein synthesis, other (non-essential) amino acid synthesis, and oxidation or transport into the portal vein [20]. This is followed by “first pass extraction” in the liver, leading to further protein and peptide synthesis and oxidation and transport into the general circulation and peripheral organs (reviewed in [20]). From a practical perspective, establishing IV access may take time in a sick, dehydrated patient, a period of time that may be precious and may be used to provide the patient with calories and nutrients. Provision of enteral feeds enables the concomitant use of an IV line for medications. Moreover, it should be remembered that it is possible to provide more calories and nutrients in a smaller volume through enteral feeds than via par-enteral nutrition. This may be particularly important when concern regarding intracranial pressure is raised and fluid volume restriction is required. Taken together, these considerations can be translated into a guideline: “If the gut is functional, use it!” We have provided enteral nutrition to patients during times of haemofiltration, once their haemodynamic state has been stabilised, with no ill effects. 8. Future perspectives Treatment recommendations for UCDs based on large scale double blind controlled studies are unlikely to be at hand because of the rarity of the disorders and the diverse treatment practices in different centres. Yet, there is a wide scope for research into a more evidence-based approach to the dietary management of patients with UCDs in large observational and comparative studies. Some of the questions that should be studied include: • Can we enhance the use of natural protein containing foods based on their respective amino acid composition and their suitability for specific UCDs? • What is the role of EAAs in the acute management of a patient with hyperammonaemia? • Can we quantify the anabolic effect of enteral vs. par-enteral nutrition in IEM? What are the limitations – if any – of using the gut for managing acute decompensation in UCDs? • Do we need to look at protein to energy ratio rather than at daily protein and energy requirements separately? What is a safe protein to energy ratio in UCDs?
These questions can be answered only through large collaborative studies, incorporating and comparing detailed records of management, compliance and outcome. Acknowledgments I wish to acknowledge the dedicated work of the dietitians Dorothy Francis, Maureen Humphrey, Judy Nation, Jamie Errico and Jemma Watkins and the students Tatijana Gardeitchick, Simon Rodney and Julia Kuypers. This work was supported by the Victorian Government's Operational Infrastructure Support Program. References [1] O. Braissant, Current concepts in the pathogenesis of urea cycle disorders, Mol. Genet. Metab. 100 (2010) S3–S12. [2] O. Braissant, Ammonia toxicity to the brain: effects on creatine metabolism and transport and protective roles of creatine, Mol. Genet. Metab. 100 (Suppl. 1) (2010) S53–S58. [3] J.V. Leonard, The nutritional management of urea cycle disorders, J. Pediatr. 138 (2001) S40–44 (discussion S44-45). [4] M. Summar, Current strategies for the management of neonatal urea cycle disorders, J. Pediatr. 138 (2001) S30–S39. [5] M. Summar, M. Tuchman, Proceedings of a consensus conference for the management of patients with urea cycle disorders, J. Pediatr. 138 (2001) S6–S10. [6] J. Haberle, N. Boddaert, A. Burlina, A. Chakrapani, M. Dixon, M. Huemer, D. Karall, D. Martinelli, P.S. Crespo, R. Santer, A. Servais, V. Valayannopoulos, M. Lindner, V. Rubio, C. Dionisi-Vici, Suggested guidelines for the diagnosis and management of urea cycle disorders, Orphanet. J. Rare Dis. 7 (2012) 32. [7] W.H.O.F.A.O.U.N.U.E.C., Joint, Protein and amino acid requirements in human nutrition, World Health Organization Technical Report Series, 2007, pp. 1–265, (back cover). [8] S. Adam, M.F. Almeida, M. Assoun, J. Baruteau, S.M. Bernabei, S. Bigot, H. Champion, A. Daly, M. Dassy, S. Dawson, M. Dixon, K. Dokoupil, S. Dubois, C. Dunlop, S. Evans, F. Eyskens, A. Faria, E. Favre, C. Ferguson, C. Goncalves, J. Gribben, M. Heddrich-Ellerbrok, C. Jankowski, R. Janssen-Regelink, C. Jouault, C. Laguerre, S. Le Verge, R. Link, S. Lowry, K. Luyten, A. Macdonald, C. Maritz, S. McDowell, U. Meyer, A. Micciche, M. Robert, L.V. Robertson, J.C. Rocha, C. Rohde, I. Saruggia, E. Sjoqvist, J. Stafford, A. Terry, R. Thom, K. Vande Kerckhove, M. van Rijn, A. van Teeffelen-Heithoff, A.V. Wegberg, K. van Wyk, C. Vasconcelos, H. Vestergaard, D. Webster, F.J. White, J. Wildgoose, H. Zweers, Dietary management of urea cycle disorders: European practice, Mol. Genet. Metab. 110 (2013) 439–445. [9] S.L. Hyman, J.T. Coyle, J.C. Parke, C. Porter, G.H. Thomas, W. Jankel, M.L. Batshaw, Anorexia and altered serotonin metabolism in a patient with argininosuccinic aciduria, J. Pediatr. 108 (1986) 705–709. [10] T. Gardeitchik, M. Humphrey, J. Nation, A. Boneh, Early clinical manifestations and eating patterns in patients with urea cycle disorders, J. Pediatr. 161 (2012) 328–332. [11] F. Scaglia, S. Carter, W.E. O'Brien, B. Lee, Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients, Mol. Genet. Metab. 81 (2004) S79–S85. [12] F. Scaglia, New insights in nutritional management and amino acid supplementation in urea cycle disorders, Mol. Genet. Metab. 100 (2010) S72–S76. [13] R.H. Singh, Nutritional management of patients with urea cycle disorders, J. Inherit. Metab. Dis. 30 (2007) 880–887. [14] M. Holecek, R. Kandar, L. Sispera, M. Kovarik, Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle, Amino Acids 40 (2011) 575–584. [15] S. Rodney, A. Boneh, Amino acid profiles in patients with urea cycle disorders at admission to hospital due to metabolic decompensation, JIMD Rep. 9 (2013) 97–104. [16] M.M. Pollack, U.E. Ruttimann, J.S. Wiley, Nutritional depletions in critically ill children: associations with physiologic instability and increased quantity of care JPEN, J. Parenter. Enter. Nutr. 9 (1985) 309–313. [17] C.H. van den Akker, F.W. te Braake, D.J. Wattimena, G. Voortman, H. Schierbeek, A. Vermes, J.B. van Goudoever, Effects of early amino acid administration on leucine and glucose kinetics in premature infants, Pediatr. Res. 59 (2006) 732–735. [18] C.T. de Betue, D.A. van Waardenburg, N.E. Deutz, H.M. van Eijk, J.B. van Goudoever, Y.C. Luiking, L.J. Zimmermann, K.F. Joosten, Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial, Arch. Dis. Child. 96 (2011) 817–822. [19] M.J. Rennie, J. Bohe, K. Smith, H. Wackerhage, P. Greenhaff, Branched-chain amino acids as fuels and anabolic signals in human muscle, J. Nutr. 136 (2006) 264S–268S. [20] B. Stoll, D.G. Burrin, Measuring splanchnic amino acid metabolism in vivo using stable isotopic tracers, J. Anim. Sci. 84 (2006) E60–E72 (Suppl.).
Please cite this article as: A. Boneh, Dietary protein in urea cycle defects: How much? Which? How?, Mol. Genet. Metab. (2014), http://dx.doi.org/ 10.1016/j.ymgme.2014.04.009
