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Volume 7.11 - 22nd June 2017

THE USE OF GLYCOMACROPEPTIDE AS AN ALTERNATIVE PROTEIN SOURCE FOR PKU Paula Hallam Registered Dietitian Paula is a Clinical Dietitian at Great Ormond Street Hospital for Children in the Metabolic Team, working predominantly with children with PKU and their families. She is also a Freelance Paediatric Dietitian, director of ‘Tiny Tots Nutrition Ltd’ and mum to two girls.

Over the past decade, there has been a growing interest in the use of glycomacropeptide (GMP) as an alternative protein source for Phenylketonuria (PKU), as it is naturally low in phenylalanine (Phe) and rich in other amino acids that are potentially beneficial.1,2,3 However, amino acid based protein substitutes have been used successfully in the treatment of PKU,4,5 so is there any need to change? A recent survey shows that patients are keen for new treatments to be developed.6 PKU is an inborn error of amino acid (AA) metabolism caused by deficient activity in the phenylalanine hydroxylase enzyme, which is needed to convert the essential AA phenylalanine (Phe) to tyrosine.1,7,8 The resulting elevated plasma Phe concentrations adversely affect the developing central nervous system, which causes profound neurological impairment and mental retardation.1 Lifelong treatment with a low phenylalanine diet results in reversal of this devastating phenotype9,10 and a ‘diet for life’ approach is recommended for all patients with PKU.11 The PKU diet consists of three main parts: 1. Restriction of natural protein to limit the amount of phenylalanine ingested to essential amounts for growth and tissue repair. The amount of natural protein allowed depends on the phenylalanine tolerance of each individual child, which is determined by the residual enzyme activity.

2. Phenylalanine-free protein substitute to provide all other essential and non-essential amino acids, as well as vitamins, minerals and trace elements. 3. Foods naturally low in phenylalanine (mainly fruits and some vegetables) and low protein foods available on prescription, to provide calories and variety in the diet. AMINO ACID BASED PROTEIN SUBSTITUTES

In the UK, it is standard practice for all children with PKU to be prescribed an amino acid based protein substitute to provide all other essential and nonessential amino acids, apart from phenylalanine.7 These protein substitutes are made from synthetic, individual amino acids and are presented as powders, liquids, pastes/gels or tablets. The specialist metabolic dietitian calculates the amount of a particular protein substitute required by a child, depending on their age, weight, metabolic control and phenylalanine tolerance.7

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NHD CPD eArticle What is glycomacropeptide (GMP)? GMP is a glycophosphopeptide comprised of 64 amino acids (AA) whose unique AA profile includes an absence of aromatic amino acids phenylalanine, tryptophan and tyrosine and higher concentrations of isoleucine and threonine, than those found in other dietary proteins.2 Commercial GMP occurs as a by-product of cheese production and contains 2.5-5mg phenylalanine per gram of protein.3,12 If GMP is to be used as a primary source of protein in PKU, it must be supplemented with arginine, leucine, histidine, tryptophan and tyrosine.2,3 Adherence issues with protein substitutes Historically, patient compliance with protein substitutes has been poor, mainly due to palatability issues, often described as having a bitter taste and strong odour.13,14 MacDonald et al15 reported that only 38% of young children took the prescribed amount of protein substitute each day, whilst Schulz et al16 found that 20% of older patients had stopped taking their protein substitutes altogether, but were still following a low protein diet. Protein substitutes are an important part of the treatment for PKU, as it has been shown that lower doses of protein substitute adversely affect blood phenylalanine control in children.14 Therefore, it is essential to find a protein substitute that is acceptable and palatable to children with PKU. GMP and palatability Protein substitutes made from GMP have been reported to be more palatable than amino acid based protein substitutes.1,17 Van Calcar et al1 reported that 10 of 11 subjects (age 11-31 years) thought the GMP products to be superior in sensory qualities to amino acid products, after consuming the GMP products for four days. In a longer study of nine weeks, Zaki et al17 found that all patients (10 children, aged four to 16

Volume 7.11 - 22nd June 2017

years) preferred the diet regime supplemented with GMP to the classical amino acid formula due to better taste and satiety. RENAL FUNCTION IN PKU

In a German study, Hennermann et al18 found impaired renal function in 19% of 67 PKU patients (aged 15 to 43 years) on a lifelong phenylalanine-restricted diet, supplemented with amino acids. They also reported proteinuria in 31%, arterial hypertension in 23% and decreasing GFR with increasing total protein intake.18 However, this has not been a consistent finding in PKU patients. Two large adult metabolic clinics in the UK have not found any evidence of decreased GFR in PKU patients (personal communication). In an eight-day inpatient metabolic study,1 the AA diet introduced a greater dietary potential renal acid load and reduced bicarbonate levels suggesting adaptations consistent with correcting for a metabolic acidosis, when compared with the GMP diet. It is hypothesised that the reported hypercalciuria18 could adversely affect bone health due to bone buffering of H+ ions, resulting in increased bone resorption.2 This theory has been supported in a study of individuals without PKU19 where the neutralizing of dietary acid load with potassium citrate for 24 months resulted in increased BMD. BONE HEALTH AND PKU

Several studies have reported low bone mineral density (BMD) in PKU patients,20,2 but the aetiology of low BMD in PKU is still unknown. A systematic review (SR) of 16 studies on BMD and fractures in PKU21 reported three studies that found significantly lower spine BMD in PKU patients compared to controls and six studies that found 20% of PKU subjects had a clinical fracture, although only one study included control subjects. Out of 12 studies of 412 PKU patients looking at phenylalanine

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The future is here

sphere

™

PKU sphere™ is available in two flavours – Vanilla and Red Berry – and is interchangeable with PKU express®, PKU cooler® and PKU air®. Suitable from 6 years of age. The lowest* calorie GMP based protein substitute available for PKU. The lowest* volume GMP based protein substitute available for PKU. The first GMP based protein substitute to be evaluated long term# in children and teenagers.1 Palatability may improve adherence in patient groups associated with wavering compliance.1

sphe re

20g PE 120

kcals

36mg

Phe

For more information about PKU sphere or to request samples for your patients with PKU, please contact your Vitaflo representative.

PKU (Phenylketonuria). GMP (Glycomacropeptide). PE (protein equivalent). Phe (Phenylalanine). 1 Data on file. *Lowest per 20g PE. #Minimum 6 months in children aged between 6 and 16 years. PKU sphere™ is a food for special medical purposes and must be used under medical supervision. For the dietary management of PKU.

Innovation in Nutrition

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NHD CPD eArticle levels and BMD, nine studies showed no correlation between raised phenylalanine levels and low BMD.21 This SR included late-treated patients which may have skewed results, as these patients are often less mobile than earlytreated patients. Another SR of bone health in PKU22 only included early-treated PKU patients. Their results suggested that patients with PKU have lower BMD than controls, but the clinical relevance of this finding is not certain, as the mean BMD was still within normal ranges as defined by the International Society for Clinical Densitometry. Bone health and GMP Solverson et al23 reported that, regardless of diet type (high-Phe casein, low-Phe AA or low-Phe GMP), whole body BMD was significantly lower in PKU compared with wild type (WT) mice. This suggests that low BMD is an inherent feature in PKU, as opposed to the diet type. However, this study also showed that the AA diet yielded a weaker and more brittle bone when compared to the GMP diet in both WT and PKU mice, illustrating that the GMP diet improved bone status.22,23 It is important to note that these were animal studies and the results cannot necessarily be extrapolated to humans with PKU. GUT HEALTH

GMP may have advantages over free amino acids on gut health, as GMP has been shown to promote the growth of beneficial bacteria in the gut of mice and piglets.22,23 In one study,1 GMP resulted in a higher concentration of total AAs in plasma and a significantly lower blood urea nitrogen, measured 2.5 hours after eating breakfast, when compared to the AA diet. This suggests slower absorption of AAs from the GMP than the AA diet and better protein retention. Amino acid formulations also have a higher osmolality than those made from whole proteins17 and this could have implications for their tolerance. GMP AND METABOLIC CONTROL

GMP products contain a source of phenylalanine - in the range of 1.5mg per gram of protein equivalent12,26 or 15mg Phe per 10g PE. Amino

Volume 7.11 - 22nd June 2017

acid protein substitutes do not contain any phenylalanine and the only source of phenylalanine in the diet is natural protein. Daly et al26 found that metabolic control deteriorated (Phe levels increased and tyrosine levels decreased) when GMP replaced AAs in children with PKU aged six to 16 years for six months. GMP could only partly replace the AA supplements due to its adverse effect on metabolic control.26 When PKU children (four to 16 years) were given their protein substitutes as 50% GMP and 50% AA, Zaki et al showed that ‘adequate’ metabolic control could be achieved.17 Although the definition of ‘adequate’ metabolic control was not clear, as the median Phe level at the start of the study was 521μmol/L (range 232-833μmol/L), which is higher than target Phe levels stated previously of, 240-360μmol/L (under 12 years) and 240-600μmol/L (for over 12 year olds). More recently, Daly et al38 has shown that if GMP and amino acid protein substitutes are titrated carefully, phenylalanine control can be maintained within the target range. OBESITY AND PKU

Many studies have reported increased rates of overweight and obesity27,28 and higher body fat percentages29 in children and adults with PKU especially in female patients, when compared with the general population. But this is not a consistent finding, as some studies found that dietary treatment for PKU did not increase the risk of obesity.30 Possible advantages of GMP on satiety in PKU It is known that protein is the most satiating macronutrient and whey protein in particular has been shown to induce satiety to a greater extent compared to other proteins.31 Ghrelin is a hormone that stimulates appetite - levels are raised in the fasted state and suppressed following a meal.31,32 GMP has been found to significantly lower postprandial plasma ghrelin concentrations, which is what you would expect following a meal. However, postprandial ghrelin concentrations after an AA based breakfast, were not different from the fasting levels taken prior to the AA breakfast.31 This study suggests a theoretical advantage of suppressing hunger for longer when PKU patients are fed GMP, when compared to AA

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NHD CPD eArticle diets. However, there was no correlation between postprandial ghrelin concentrations and BMI. There is also no evidence that GMP will improve weight management in PKU in the long term as no long-term studies have been reported. Energy value of protein substitutes GMP products from the USA have a mean energy value of 180kcals (range 107-220kcals) per 10g protein equivalent (PE), not including the recent ‘Lite’ versions of the GMP products. This is compared with an average of 81kcals (range 44-135kcals) per 10g PE in the amino acid based protein substitutes available in the UK. It could be hypothesised that the higher energy values in the GMP products could contribute to the level of obesity seen in PKU. LARGE NEUTRAL AMINO ACIDS (LNAAS)

Studies have shown that the use of LNAAs could be useful in the management of PKU.35,2 Oral LNAA supplementation has been shown to reduce brain Phe concentrations and improve neuropsychological functioning in adults.34 As LNAAs share a common transporter, they can compete with Phe at the level of the gut and blood brain barrier thereby reducing absorption and entry of Phe into the brain. If the transporter was saturated with other AAs, then less Phe would enter the brain.33,34 The goal of dietary management of PKU is to lower plasma Phe levels, which in turn lowers brain Phe. It is this lower brain Phe that is thought to prevent the damage to the developing brain.33 GMP is rich in LNAAs isoleucine and threonine; with levels being two to three fold higher than those found in other dietary proteins.35 In a study of PKU mice fed AA diets and GMP diets for 47 days, the PKU mice fed the GMP diet had an 11% decrease in plasma Phe levels and a 20% decrease in brain Phe concentrations, when compared to PKU mice fed an AA diet.35 Threonine, given as a dose of 50mg/kg, has been shown to reduce plasma Phe concentrations in humans with PKU,36 although the mechanism for this is not completely understood. In a study of 11 PKU subjects (adults and children), there was a variable response in plasma phenylalanine concentrations after being on the GMP diet for four days, compared with

Volume 7.11 - 22nd June 2017

the AA diet.1 There was a mean change of 57 +52umol/L in Phe concentrations, but this ranged from a decrease of 157umol/L to an increase in 257umol/L Phe. In this study,1 the GMP diet resulted in a mean fasting tyrosine concentration that was below the normal range. In a study of 21 children with PKU (mean age 11 years, range six to 16 years), the addition of LNAAs to a modified GMP protein substitute improved metabolic control - median blood Phe results were unchanged and medium tyrosine results were higher, when compared to results from 12 months prior to the study on an amino acid-based protein substitute.37 SUMMARY

There are documented palatability issues with amino acid protein substitutes in children with PKU and GMP offers an alternative, more palatable protein source. However, GMP contains residual Phe and this has been shown in one study to have a detrimental effect on metabolic control in children with PKU. But this deleterious effect can be attenuated by the addition of LNAAs to GMP products. One study reported impaired renal function in adults with PKU on a lifelong Phe restriction supplemented with amino acid protein substitutes, but this has not been consistently reported in other PKU centres around the world. In an eight-day study, a diet supplemented with GMP was shown to decrease the dietary acid load in PKU patients, but the clinical relevance of this finding is not very clear. It has been hypothesised that hypercalciuria could be contributing to the low BMD seen in PKU due to bone resorption, but other studies have suggested that the low BMD seen in PKU is inherent to the disease itself. GMP may have advantages for gastrointestinal health as it has been shown in animal studies to promote the growth of beneficial bacteria in the gut. GMP is also absorbed at a slower rate than amino acids, which may be beneficial for protein retention and feelings of satiety. GMP has also been shown to lower appetite stimulating hormones, thereby decreasing hunger in PKU patients. This may have implications for improving obesity rates, which are high in PKU patients, particularly in females. Although no

NHD CPD eArticle association has been shown between decreased appetite stimulating hormone levels and BMI. Conversely, GMP products for PKU tend to be high in calories and this could worsen the obesity seen in PKU patients. GMP is very high in the LNAAs isoleucine and threonine, which are known to be beneficial to PKU patients by competing with Phe at the blood brain barrier and thereby decreasing brain Phe levels. Amino acid protein substitutes also contain LNAAs, but not to the level as those present in GMP products.

Volume 7.11 - 22nd June 2017 OVERALL CONCLUSION

GMP offers several advantages over AA as an alternative protein source for children with PKU. However, issues around metabolic control due to residual Phe in GMP, need to be resolved. Considering the evidence to date, I suggest that GMP could partly replace traditional AA protein substitutes, without compromising metabolic control, in those children/adults who are struggling with the palatability of their AA protein substitutes.

References 1 Van Calcar et al. Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids. Am J Clin Nutr 2009: 89; 1068-77 2 Ney DM et al. Advances in the nutritional and pharmacological management of phenylketonuria. Curr Opin Clin Nutr Metab 2014: 17(1); 61-8 3 LaClair et al. Purification and use of glycomacropeptide for nutritional management of phenylketonuria. J Food Sci 2009: 74 (4); E199-E206 4 Aguiar et al. Practices in prescribing protein substitutes for PKU in Europe: No uniformity of approach. Mol Genet Metab. 2015 May; 115(1): 17-22 5 Al Hafid N, Christodoulou J. Phenylketonuria: a review of current and future treatments. Transl Pediatr. 2015 Oct; 4(4): 304-17. 2224-4336 6 Brown CS, Lichter-Konecki U. Phenylketonuria (PKU): A problem solved? Mol Genet Metab Rep. 2015 Dec 29; 6:8-12 7 Clinical Paediatric Dietetics, 4th Edition. Edited by Vanessa Shaw. 2015. John Wiley and Sons Ltd 8 Mitchell JJ. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2013 Jan 31]. In: Pagon RA, Adam MP, Ardinger HH et al. Editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016 9 O’Flynn ME, Holtzman NA, Blaskovics M et al. The diagnosis of phenylketonuria: a report from the Collaborative Study of Children Treated for Phenylketonuria. Am J Dis Child. 1980 Aug; 134(8): 769-74 10 Koch R, Burton B, Hoganson G et al. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis. 2002 Sep; 25(5): 333-46 11 Nardecchia F et al. Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: A longitudinal study. Mol Genet Metab. 2015 Jun-Jul; 115(2-3): 84-90 12 MacDonald A, Godmen-Ozel H, Daly A. Changing dietary practices in phenylketonuria Turkish J of Ped 2009; 51: 409-15 13 MacDonald A. Diet and compliance in phenylketonuria. Eur J Ped 2000, 159 (suppl) S136-141 14 Macdonald A, Daly A, Davies P et al. Protein substitutes for PKU: what’s new? J Inherit Metab Dis. 2004; 27(3): 363-71 15 MacDonald A et al. Abnormal feeding behaviours in phenylketonuria. J Hum Nutr Diet 1997; 10: 163-170 16 Schulz B and Bremer HJ. Nutrient intake and food consumption of adolescents and young adults with phenylketonuria. Acta Paediatrica 1995; 84: 743-8 17 Zaki et al. The use of glycomacropeptide in dietary management of phenylketonuria. J Nutr Metab; Epub 2016 May 30 18 Hennermann JB et al. Chronic kidney disease in adolescent and adult patients with phenylketonuria. J Inherit Metab Dis. 2013 Sep; 36(5): 747-56 19 Jehle S et al. Effect of potassium citrate on bone density, microarchitecture and fracture risk in healthy older adults without osteoporosis: a randomised controlled trial. J Clin Endocrinol Metab. 2013 Jan; 98(1): 207-17 20 De Groot MJ et al. Relationships between lumbar bone mineral density and biochemical parameters in phenylketonuria patients. Mol Genet Metab. 2012 Apr; 105(4): 566-70 21 Hansen KE and Ney D. A systematic review of bone mineral density and fractures in phenylketonuria. J Inherit Metab Dis 2014; 37(6): 875-80 22 Demirdas S et al. Bone health in phenylketonuria: a systematic review and meta-analysis. Orphanet Journal of Rare Diseases 2015; 10: 17 23 Solverson et al. Low bone strength is a manifestation of phenylketonuria in mice and is attenuated by a glycomacropeptide diet. PLoS ONE 7(9): e45165 24 Hermes et al. Casein glycomacropeptide in the diet may reduce Escherichia coli attachment to the intestinal mucosa and increase the intestinal lactobacilli of early weaned piglets after an enterotoxigenic E. coli K88 challenge. British Journal of Nutrition (2013), 109, 1001-1012 25 Sawin et al. Glycomacropeptide is a prebiotic that reduces Desulfovibrio bacteria, increases cecal short-chain fatty acids and is anti-inflammatory in mice. Am J Physiol Gastrointest Liver Physiol. 2015 Oct 1; 309(7): G590-601 26 Daly et al. Glycomacropeptide: can we safely advocate its use in children with PKU? J Inherit Metab Dis 2015; 38 (suppl 1): S39-40 27 Burrage et al. High prevalence of overweight and obesity in females with phenylketonuria. Mol Genet Metab. 2012 Sep; 107(1-2): 43-8 28 Robertson et al Body mass index in adult patients with diet-treated phenylketonuria. J Hum Nutr Diet. 2013 Jul; 26 Suppl 1: 1-6 29 Albersen et al. Whole body composition analysis by the BodPod air-displacement plethysmography method in children with phenylketonuria shows a higher body fat percentage. J Inherit Metab Dis (2010) 33 (Suppl 3): S283-S288 30 Rocha et al Dietary treatment in phenylketonuria does not lead to increased risk of obesity or metabolic syndrome. Mol Genet Metab. 2012 Dec; 107(4): 659-63 31 MacLeod et al. Breakfast with glycomacropeptide compared with amino acids suppresses plasma ghrelin levels in individuals with phenylketonuria. Met Genet Metab 2010; 100 (4): 303-8 32 Schulpis et al. Morning preprandial plasma ghrelin and catecholamine concentrations in patients with phenylketonuria and normal controls: evidence for catecholamine-mediated ghrelin regulation. J Clin Endo Metab 89(8); 3983-7 33 Strisciuglio P and Concolino D. New Strategies for the Treatment of Phenylketonuria (PKU) Metabolites 2014, 4, 1007-1017 34 Schindeler et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Gen Metab 2007: 91; 48-54 35 Ney et al. Dietary glycomacropeptide supports growth and reduces the concentrations of phenylalanine in plasma and brain in a murine model of phenylketonuria. 2008. J Nutrition 138: 316-22 36 Sanjurjo P, Aldamiz L, Georgi G, et al. Dietary threonine reduces plasma phenylalanine levels in patients with hyperphenylalaninemia. J Pediatr Gastroenterol Nutr. 2003; 36:23-26. 37 MacDonald A, Daly A, Chahal S, Evans S. Impact of residual phenylalanine and large neutral amino acid profile of casein glycomacropeptide on metabolic control in children with PKU. Abstract at BIMDG 30 June - 1 July 2016 38 Daly A, Evans S, Chahal S, Santra S and MacDonald A (2017). Glycomacropeptide in children with phenylketonuria: does its phenylalanine content affect blood phenylalanine control? J Hum Nutr Diet. doi:10.1111/jhn.12438 Copyright © 2017 NH Publishing Ltd - All rights reserved. Available for printing and sharing for the use of CPD activities for personal use. Not for reproduction for publishing purposes without written permission from NH Publishing Ltd.

NHD CPD eArticle NETWORK HEALTH DIGEST

Volume 7.11 - 22nd June 2017

Questions relating to: The use of glycomacropeptide as an alternative protein source for PKU. Type your answers below, download and save or print for your records, or print and complete by hand. Q.1

What is the aetiology of phenylketonuria (PKU)?

Q.2

Explain the PKU diet.

Q.3

Why are protein substitutes an important part of nutrition management in PKU?

Q.4

What is glycomacropeptide (GMP)?

Q.5

Explain why patient compliance to protein substitutes has been poor in the past.

Q.6

Can GMP have an effect on bone health in patients with PKU?

Q.7

Describe the relationship between GMP and metabolic control.

Q.8

What are the advantages of GMP on satiety in PKU?

Please type additional notes here . . .