Management
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PKU Nutrition Management Guidelines
First Edition
March 2015, v.1.12
Updated: August 2016
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Nutrition Recommendations
Question
3. For individuals with PKU which nutrition interventions are associated with positive outcomes?
Conclusion Statement
Derived from evidence and consensus based clinical practice

Individuals with PKU who adhere to treatment that maintains blood PHE within the recommended treatment range of 120-360 µmol/L throughout their lifespan have optimal outcomes as measured by quality of life, neurocognitive development, and nutritional and medical well-being. Adherence to the complex treatment is improved by various intervention strategies. No single strategy, or combination of strategies, is appropriate for all individuals under all circumstances. Healthcare providers should partner with the individual in decisions regarding choice of medical food and timing of intake, use of breast milk or formula by bottle or feeding from the breast, timing and process of weaning, means of tracking and adjusting dietary PHE, and coping strategies for adhering to diet when away from home. Educational or instructional opportunities must be individualized to the individual’s or caregiver’s educational level, cultural norms, experience, motivation, and financial resources. Age-appropriate instruction can help children begin to assume responsibility for diet management, and guide adolescents in the transition from a pediatric to adult clinic. Effort must be made to assure all patients have access to appropriate care, monitoring, and medical and low-protein foods. Identifying off-diet adults and encouraging initiation or resumption of treatment has proven difficult, but those who have been able to reduce blood PHE have had positive outcomes.

Recommendation 3.1

Choose medical foods to meet recommended nutrient intake and achieve optimal adherence. When incomplete medical foods are chosen, ensure that vitamin, mineral, energy, and/or fat intake is supplemented from other sources when necessary.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Because individuals with PKU must often meet 75-85% of their protein allowance from medical food (F.2626F.2627, F.2729, F.1344), selection of an appropriate medical food is important for maximizing adherence to the dietary prescription and achieving optimal nutrient intake. However, choices for a given individual may be limited by state regulations and the extent of third party reimbursement (F.1465). Classification of medical foods is described in TABLE #6, Classification of Medical Foods for PKU, and includes categories for specific age groups and for "completeness" of the products. Medical food is defined as incomplete when it does not contain either vitamins, minerals, fat and/or carbohydrates. Newer product formulations, such as ready-to-drink options, have found acceptance and demonstrated short term increased compliance with medical food intake (F.1254, F.2460). The sense of taste is imprinted early, so there may be poor acceptance of some medical foods by individuals who are late-diagnosed or returning to diet (F.2518). Improvements in flavor have been made possible by removing the vitamin and mineral supplementation found in most medical foods. However, a recent study (F.1317) showed that compliance in taking a separate vitamin/mineral supplement, in conjunction with the "incomplete" medical food, decreased over time (F.1317). See TABLE #7, Recommendations for Nutrient Intake and Sources in the Dietary Treatment of PKU for recommended nutrient intakes and sources of nutrients appropriate for treatment.

Consensus based on clinical practice

In Delphi I, there was strong agreement (91% RD and 100% MD respondents) that individuals with PKU consuming medical foods without added vitamins or micronutrients should be supplemented.

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Evidence

Medical foods incorporating LNAA have been investigated for use in non-pregnant adults who have been unsuccessful in adherence to other dietary treatments for PKU (F.2626, F.2627, F.2629). Commonly, individuals using LNAA products derive approximately 20-30% of their PRO needs from the LNAA and 70-80% from intact protein in dietary sources (F.2627, F.2629). In a recent six month study of 6 adults consuming LNAA, there was no improvement in blood PHE, but there were increases in blood TYR, decreases in brain PHE, and the subjects reported "feeling better" (F.2236). See further discussion in Question 5.

Consensus based on clinical practice

In Delphi 1, most respondents agreed (82% RD and 80% MD) that it was appropriate to consider the use of LNAA in individuals over the age of 18 years.

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Evidence

GMP is an intact protein, found in whey, that is naturally low in PHE. See TABLE #6, Classification of Medical Foods for PKU for classification of medical foods. Studies of GMP as the protein source in medical foods have demonstrated early taste acceptance by individuals with PKU (F.1138, F.1172, F.1520). GMP is also appropriate for incorporation into products other than beverages. This may facilitate the ability to spread intake throughout the day (F.1520). It has also been shown to increase grehlin production, and thus satiety, that could benefit individuals who experience feelings of hunger when adhering to a PHE-restricted diet (F.1168). GMP-based products have been reported to cause a rise in plasma amino acids that should support normal growth (G.107). GMP, as a by-product of cheese production, has been investigated as a viable lower cost alternative to amino acid-based medical foods in countries outside the US (F.1144)

Consensus based on clinical practice

In Delphi 1, all respondents were neutral to the statement that GMP-based medical foods demonstrate nutritional superiority, greater satiety and palatability. Comments showed a lack of experience with these products.

Recommendation 3.2

Advise consumption of medical food throughout the day, in several well-spaced intervals, to allow optimal blood PHE concentrations and dietary PHE tolerance.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Numerous studies have shown that increasing the number of times medical food is consumed over a 24 hour period improves both blood PHE and dietary PHE tolerance (F.2627, F.2629, F.679, F.1241, F.2241, F.2561). Although receiving medical food throughout a 24 hour period was recently shown to have the greatest impact on blood PHE and PHE tolerance, the impracticality of that method is recognized, and it is suggested that a time-release product may accomplish the same outcome (F.2241). Generally recommendations are for three, well-spaced, intervals (G.102, G.109). In infants with PKU, no significant difference in blood PHE levels was observed when medical food and regular infant formula/breast milk was given in alternating feedings (F.679). However, it must be recognized that infants normally have multiple feedings both day and night.

Consensus based on clinical practice

In Delphi 1, 100% of respondents agreed that medical food should be taken at least three times throughout the day.

Recommendation 3.3

Encourage use of breast milk, when possible, either from direct breast feeding or use of expressed breast milk, as the source of PHE (and intact protein) in infants.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Breast milk is an appropriate source of intact PRO and PHE for infants with PKU when the mother is able to provide adequate amounts and the infant's blood PHE can be monitored closely (F.2627). Good metabolic control has been shown to be possible using either expressed breast milk or feeding at the breast (F.2627, F.907, F.1180, F.2542) and various strategies have been offered (G.102, G.109). In addition, higher long chain polyunsaturated fatty acids concentrations (LCPUFA) were found in infants with PKU who had early exposure to breast milk and these same infants had slightly better visual function at 12 months of age (F.2228). However, the number of infants with PKU being breast fed is considerably less than seen in the general population, so encouragement and support for mothers of these infants is necessary (F.2517). In Europe, all but 2 countries encourage breast feeding or the use of breast milk (F.2542). Clinics in those two countries cite limited access to both supportive health care providers and monitoring (F.2542). 

Consensus based on clinical practice

In Delphi 1, the greatest consensus among respondents (82% RD and 67% MD) was to include breast milk as part of the intake for infants with PKU by alternating feedings between medical food bottles and direct breast feeding. Consensus from respondents for other methods of using breast milk was: mixing expressed breast milk and medical food in each bottle for each feeding (55% RD and 67% MD) and feeding a bottle of medical food, followed by ad lib breast feeding at each feeding (73% RD and 20% MD).

Recommendation 3.4

Gradually introduce solids, to replace the equivalent amount of PHE/intact protein in infant formula or breast milk, when the infant is developmentally ready (usually at 4-6 months of age).

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Most infants with PKU, like those in the general population, have appropriate developmental skills to begin to accept solid foods between 4-6 months of age (F.2627, F.1008). Clinics in the UK have reported success with introducing solids first as a paste/slurry of medical food to allow the infant to become used to the texture and to the spoon before introducing new flavors (F.1008). In order to keep dietary PHE intake consistent and maintain good blood PHE control, the intact protein from either breast milk or regular infant formula should be gradually removed from the formula mix and replaced with an equivalent amount of PHE from appropriate solid foods (F.2627, G.102, G.109), beginning with 15-45 mg PHE provided from solids (G.109). If an infant >12 months of age cannot meet all the PHE allowance with solid food, additional PHE can be provided from precise amounts of soy or cow’s milk rather than infant formula. The authors of the UK study advise against over-prescribing medical food to infants, as this has been shown to delay acceptance of solids (F.1008). They also suggest that studies are needed to provide evidence-based guidelines for weaning.

Consensus based on clinical practice

In Delphi 1, there was agreement (82% RD and 83% MD respondents) that replacing the PHE provided by breast milk or regular infant formula with solid foods, starting with15-30 mg PHE per day, was appropriate for infants with PKU.

Recommendation 3.5

Minimize elevation of blood PHE during illness by treating the underlying illness, meeting protein and energy needs, and preventing dehydration and electrolyte imbalance.

 

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

No specific studies evaluating dietary treatment for individuals with PKU during illness have been reported. However, author opinion from a recent extensive review (F.2627) and consensus opinion obtained as part of this guideline's evidence gathering agreed that priorities are to: treat the underlying illness, minimize protein catabolism and encourage anabolism by providing adequate energy to spare endogenous protein, and further restrict dietary intact PRO/PHE in order to manage blood PHE concentrations. Successful use of a total parenteral nutrition solution that included a PHE-free module has been reported in two recent cases of individuals who were unable to be fed enterally (F.1512, F.1209). Adequate energy intake can be accomplished with sweetened beverages, PHE- free foods, or PRO-free medical foods. If medical food is refused, it should be reintroduced as soon as possible, first using 1/2 strength if full strength is not well tolerated (G.102)

Consensus based on clinical practice

In Delphi 1, there was no consensus for the necessity of decreasing dietary PHE intake by 50% during illness.

In Delphi 2, 90% of respondents agreed that, in individuals with PKU, treatment of the underlying illness should be prioritized, and 95% agreed with the recommendation to maintain usual medical food intake during illness, if tolerated. There was less agreement (71%) among respondents to increase energy intake and decrease PHE intake during illness in response to elevated blood PHE.  Comments suggest that delay in obtaining blood PHE reports makes it difficult to make dietary changes during illness in response to blood PHE concentrations.

In the Nominal Group, 88% of participants agreed that neither proactively reducing blood PHE, nor reducing PHE intake in response to elevated blood PHE concentrations, was needed in treating individuals with PKU during inter-current illness.

Recommendation 3.6

Ensure appropriate PHE intake in individuals with PKU by having accurate data regarding PHE content of foods, and effective and convenient methods of planning and monitoring dietary PHE intake.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Because an individual with PKU cannot catabolize excess PHE, it is important to provide only the amount of dietary PHE essential for anabolism and achievement of appropriate blood PHE concentrations. This requires knowing the PHE content of foods, having a means to track and plan PHE intake on a daily basis, and being able to adjust PHE intake when blood PHE concentrations are out of range (F.2627). Accurate nutrient analysis of foods is necessary (F.2400), along with calculation platforms such as MetabolicPro ( https://metabolicpro.org). Most US clinics have adopted the strategy of counting total milligrams PHE or using an exchange system where one exchange equals 15 mg PHE for individuals with classical or moderate PKU, and a more relaxed counting of grams of PRO for those with have mild PKU (F.2627). A growing number of clinics, especially outside the US, have adopted a system that allows low PHE fruits and vegetables to be consumed freely and a limited, but defined, amount of PRO allowed from higher PHE foods (F.1506, F.1529). A two week study in Germany of 14 children who began tracking and planning PHE intake based on free intake of fruits and vegetables showed no significant change in blood PHE concentrations compared to when they were counting all sources of PHE. Surprisingly, the children did not increase their intake of fruits and vegetables, but "used" their extra PHE allowance to consume higher PHE foods (F.1506). Using a similar counting system (where foods were considered free if the PHE content <100 mg/100 gm food), 80 Swiss individuals were followed for 2 years. Blood PHE concentrations were not significantly different in the <10 years old age group, or the >18 years old age group, but were significantly higher in the adolescent group (F.1529).

It has been suggested that since PKU is a chronic disease, some treatment strategies developed for other chronic diseases could be adapted for PKU treatment (F.1478). Home monitoring of blood PHE (i.e. "PHE monitors") may improve diet management as glucose monitoring does for diabetes (F.2204).

Consensus based on clinical practice

In Delphi 1, there was strong agreement among respondents (82% RD and 100% MD) that tracking dietary PHE is key to managing PKU. Consensus regarding the amount of change in dietary PHE intake based on blood PHE concentrations was as follows: if blood PHE is 360-600 µmol/L reduce dietary PHE intake by 10% (82% RD and 60% MD), if blood PHE is >600 µmol/L reduce dietary PHE intake by 20-25% (73% RD and 60% MD), and if blood PHE is <120 µmol/L increase dietary PHE by 10-20% (100% RD and 80% MD).

In Delphi 2, there was strong agreement among all respondents (81%) that adults could maintain recommended blood PHE by tracking dietary intake with grams PRO rather than milligrams PHE, but agreement fell sharply the younger the age group being considered. Comments from many respondents stated that knowing PHE tolerance of the individual being considered was an important consideration, and that individuals with low PHE intake tolerance required more careful tracking (PHE instead of PRO).

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Evidence

Individuals with PKU who have a low PHE tolerance often depend on modified low-protein foods to provide added energy, bulk, variety, and normal appearance to their diets (G.106). These specialty foods, including low-protein baked goods and pastas, use the starch portion of grains rather than higher-protein flour or whole grain. They do not provide vitamin enrichment found in regular grain products. Access to these foods may be limited by cost, availability primarily by mail order, and third party reimbursement that is not universal (F.1465, F.2627).

Consensus based on clinical practice

In Delphi 1, most respondents agreed (82% RD and 100% MD) that individuals with genotypes associated with very low PAH activity have a greater reliance on modified low protein foods (as well as on medical foods).

Recommendation 3.7

Encourage all individuals to follow treatment recommendations throughout their lives; including those who have relaxed their diet restrictions and those who have never been treated. Recognize and address individual barriers that may impede success.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Most recent recommendations state that individuals with PKU should follow a PHE-restricted "diet for life" (F.2626, F.2627, F.2629). This includes initiating PHE restriction for those who were late-diagnosed or never treated, and re-introducing treatment for those who relaxed or discontinued PHE restriction. It is known that individuals with untreated PKU are at risk for: neurocognitive disability, abnormal psychiatric profile, eczema, unusual body odor, and poor socialization (F.2626F.2627, F.2629). For late- or never-treated individuals, there are a number of recent reports that describe symptoms such as poor growth with shorter stature, disproportionate body parts (F.1200), significant intellectual impairment, and psychosocial maladjustment (F.1236). In a review of 11 studies (F.2255) most individuals reported improvement in many aspects of their lives when PHE restriction was implemented.

Consensus based on clinical practice

In Delphi 1, there was strong agreement (91% RD and 100% MD respondents) that previously untreated adults with PKU should be offered a PHE-restricted diet, and/or the possibility of adjuvant therapies. See further discussion in Question 5.

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Evidence

Barriers to treatment adherence for the individual with PKU have been identified in several recent studies. It has been demonstrated that frequency of blood PHE monitoring and contacts with clinic personnel diminish as the individual ages. More importantly, adherence to dietary recommendations decreases and results in an increase in mean blood PHE (G.109, F.2626, F.2629, F.2627, F.925, F.1297, F.1392). Barriers to adherence include: limited access to age-appropriate care, laboratory monitoring, and medical food; as well as failure to understand basic diet management or believe in its effectiveness (F.2626, F.2627). Other barriers include lack of appropriate social support systems, and inability to manage food restrictions and medical food consumption while at work, or school, or in social situations (F.1465, F.2390, F.1312). In individuals old enough to self-manage, a certain amount of apathy coincides with high blood PHE concentrations and this, itself, becomes a barrier to dietary compliance (F.1431).

At all ages, there are medical and health barriers that may require modification of the typical PHE-restricted diet. Obese patients, treated with gastric bypass, have been described who have successfully managed treatment requirements immediately after surgery with liquid diets, and long-term with appropriate blood PHE concentrations (G.90). Some individuals are reported to have improved exercise tolerance and built muscle mass with use of creatine, while being closely monitored for blood PHE concentrations and kidney function (G.89). Other barriers to adherence include: anxiety of parents, need to educate multiple caregivers, expense of specialized foods/medical food, poor acceptance of medical food, maintenance of diet at school/job, frequent monitoring and clinic visits, psychosocial problems that may develop with high blood PHE, and generally coping with a chronic disease (G.109).

Locating adults with PKU who have been lost to follow up has been shown to be difficult (F.899, F.2365). In a recent study, the number of off-diet or never-treated older individuals who were successfully identified and contacted was far less than incidence numbers would suggest (F.2365). It is estimated that in the US, 77% of adults with PKU between the ages of 25-45 are not adherent to dietary treatment (F.1415).

Consensus based on clinical practice

In Delphi 1, there was agreement in 100% of respondents that psychosocial support improves adherence to treatment recommendations for individuals with PKU. In addition there was 100% agreement that individuals with PKU need access to care, medical foods and psychosocial services.

Recommendation 3.8

Adopt clinic procedures that enhance adherence to the nutritional recommendations of “diet for life” by providing individualized educational strategies, referrals to appropriate social service and mental health professionals, age-appropriate group activities, and a plan for transition from pediatric to adult clinical services.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Various clinics have recently reported strategies that improved individual adherence. These include: home visits (F.2334), home delivery of medical food products (F.2403), integration between the metabolic clinic and mental health services (F.1473, F.1477), inclusion of social services in the metabolic team (F.2583), and simplification of dietary PHE tracking (F.1506, F.1529).

One of the predictors of long-term adherence is stable and appropriate blood PHE concentrations in children during the period from 0-3 years of age (F.2357). Usually this is the period of most frequent interaction with health care professionals and intensive education of parents (F.925). Although educational level of parents appeared to be significant in determining level of adherence in some studies (F.2357, F.2535), other recent studies have shown that the knowledge level of parents is a better predictor of outcome (F.2553, F.1499, F.2548).

Educational tools and strategies must be individualized based on the needs (age, educational level, language, socio-economic status, cultural norms) of the parents/caregivers and, later, of the individual with PKU him- or herself ( F.1513, F.2553, F.1499, F.2548, F.2583).Studies have indicated that there is no one successful strategy, but educational tools and supportive activities must be adapted (F.2390) to individual needs. While most education is directed toward parents and other caregivers when the child with PKU is young, all agree that the gradual transfer of responsibility for management should begin early. Age specific educational activities are important (F.927). 

Several strategies have been employed to locate “off-diet” adults with PKU to assess health status and encourage a return to treatment. These included outreach to a wide range of health professionals to help identify individuals with a diagnosis of PKU (F.2365) and an announcement in a large city newspaper of an event for adults with PKU (F.899). Although these strategies did not yield large numbers, there were some individual successes (F.899). Continuous and individualized education, community support, and removal of barriers to access to care and essential medical food products are found to be important in helping individuals with PKU maintain lifelong treatment.

Consensus based on clinical practice

In Delphi 1, there was agreement in 100% of respondents that psychosocial support improves adherence to treatment recommendations for individuals with PKU. In addition there was 100% agreement that individuals with PKU need access to care, medical foods and psychosocial services.

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Evidence

Transition refers to a specific process of transferring care of the individual with PKU from a pediatric- to an adult-centered program (F.2626, F.2627), while assuring attention to medical, psychosocial, educational, and vocational needs of youth and young adults (F.2629). Transition programs have been implemented for a number of chronic disorders where diagnosis and treatment begins at birth or in childhood and is lifelong (F.1187). Maintaining adolescents and young adults with PKU on dietary therapy requires a well-designed plan for transition. Successfully engaging adolescents in the transition process by seeking their input has been reported (F.1431, F.2539). Adolescents and young adults have identified the need to learn more practical skills for diet management, and coping skills for integrating the diet into a normal lifestyle (F.1503). When professional caregiving personnel are limited, peer support groups and activities can be helpful (F.1187). Survey results from 48 patients who participated in a transition program in the U.K. indicated a significant improvement in blood PHE concentrations and number of individuals (92%) “on diet” one to three years after the transition (F.2533).  Important components of successful transition were identified as continuous contact with the clinic and coordination between the pediatric and adult healthcare providers (F.2533).

Consensus based on clinical practice

In Delphi 1, there was strong agreement (100% RD and 80% MD respondents) that clinics should provide transition from pediatric to adult care.

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