Overweight in Phenylketonuria
Júlio César Rocha
Nutritionist, PhD
Centro de Genética Médica JM, CHP EPE, Porto, Portugal
Faculdade de Ciências da Saúde, UFP, Porto, Portugal
Center Health Technology Services Research (CINTESIS), Porto, Portugal
[email protected]
Phenylketonuria (PKU; MIM 261600) is an inborn error of amino acid metabolism caused by reduced
phenylalanine hydroxylase (PAH; EC 1.14.16.1) activity (Blau et al 2010). After the discover by Dr.
Asbjørn Følling (Folling 1994), the first treatment approach was proposed by Dr. Horst Bickel in
1950s (Bickel et al 1953). Despite new therapies have recently emerged [large neutral amino acids
(LNAA), Glycomacropeptide (GMP) and Sapropterin (BH4)] (Ney et al 2014), the proposed dietary
phenylalanine (Phe) restriction is still the mainstay of treatment for patients with PKU. This is
achieved through a natural protein restricted diet giving simultaneously a Phe-free amino acid mixture
(protein substitute), nowadays enriched with vitamins and minerals (Giovannini et al 2012). In order
to satisfy patient’s energy needs and to improve dietary compliance, special low protein foods are
currently available for inclusion in the diet. The nutritional composition of these foods reveals a
significant richness in carbohydrates and fat, while protein and Phe content are almost negligible
(Rocha et al 2007).
When diet is implemented in the first weeks of age and treatment is adequately continued, mental
retardation is avoided which constitutes an important conquest comparing to the picture usually seen
before newborn screening programs implementation (Blau et al 2011). The tremendous success of
this dietary treatment opened new horizons and a careful nutritional status management is nowadays
recommended for these patients. An adequate growth promotion was naturally considered one of the
major objectives, although its interpretation may not be straightforward in diseases like PKU
(MacDonald et al 2011). In fact, the major protein ingestion of patients with PKU is derived from the
chemically manufactured protein substitutes. The efficacy and bioavailability of these protein
substitutes seems to be lower than of intact protein which probably justifies the extra nitrogen intake
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suggested for these patients (MacDonald et al 2011). Classical forms of the disease, under reduced
natural protein intakes, seem to have a less favorable growth outcome (Rocha et al 2013). However,
BH4-treated patients may also manifest growth impairment, despite their increased natural protein
tolerance, sometimes may allow a normal diet (Aldamiz-Echevarria et al 2013). Again, since growth
is a complex physiologic phenomenon not only dependent on protein intake (Lifshitz 2009), further
studies are desirable in PKU (Dokoupil et al 2012).
Considering the food pattern characteristics, particularly the high energy intake to promote anabolism
(Dobbelaere et al 2003; Huemer et al 2007), the interest on the energetic balance and on the
concomitant consequences in terms of obesity development has been increasing (Giovannini et al
2012). Early studies in the USA reported a tendency to overweight in PKU (Holm et al 1979; White
et al 1982; McBurnie et al 1991). The same tendency was also underlined one decade later by the
study from Acosta and co-workers (Acosta et al 2003). In Europe, the prevalence of overweight
within Italian patients with HPA and PKU was 25% at the age of 8 years (Scaglioni et al 2004). More
recently, this issue was underlined again at least during adolescence (Belanger-Quintana and
Martinez-Pardo 2011), particularly in females (Burrage et al 2012) and specially when dietary
compliance was poor (Doulgeraki et al 2014). Although a tendency for a higher prevalence of
overweight was found in UK female adults (Robertson et al 2013), global prevalence of overweight
and obesity does not seem to differ from the general population (Rocha et al 2012; Robertson et al
2013).
Finding similar overweight prevalence in PKU and general population should not be viewed linearly
as a positive result. In fact, patients with PKU are constantly under nutritional advice, and health care
professionals should make all the efforts to prevent overweight development. Overweight and obesity
are usually associated with several cardiometabolic markers that increase the risk of cardiovascular
disease and type 2 diabetes (Despres and Lemieux 2006; Van Gaal et al 2006). Reaven (Reaven 1988)
proposed the metabolic syndrome (MetSyn) concept where insulin resistance would be on the basis
of the aggregation of other abnormalities related with blood pressure, high density lipoproteincholesterol (HDL-c), triglycerides (TG) and glucose. Several other definitions have been developed
by different organisms like World Health Organization (WHO) (Alberti and Zimmet 1998), the
National Cholesterol Education Program Adult Treatment Panel III (Grundy et al 2004), the European
Group for the Study of Insulin Resistance (Balkau and Charles 1999) and more recently the
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International Diabetes Federation (Alberti et al 2005). Although the physiopathology of MetSyn has
not been clarified yet, insulin resistance and central obesity (Despres and Lemieux 2006) are
considered major factors. In addition, the presence of atherogenic dyslipidemia, characterized by
increased TG and reduced HDL-c, is also relevant (Alberti et al 2006).
In PKU it is unknown if obesity etiology is a result of the underlying condition, a treatment
consequence, or an outcome of inadequate metabolic control. Birth weight and parental weight are
well known contributing factors, justifying a careful interpretation of these data. Also, an early body
mass index rebound in infancy is also a determinant factor for later obesity development and should
also be prevented in PKU (Scaglioni et al 2004). Regarding disease severity, there are conflicting
data in the literature and, at this moment, it is not possible to clarify whether classical forms of the
disease would be more susceptible for overweight development (Rocha et al 2013). Another aspect
that should be analyzed in each cohort of patients is the existence of growth impairment. Some studies
have been reporting this and its consequences in terms of overweight development later in life should
be taking into account. Beyond this factor, the modifiable dietary factors should also be analyzed, in
order to prevent weight rise, but also metabolic comorbidities, particularly central obesity and
dyslipidemia (Rocha et al 2012; Kanufre et al 2015). Overweight has a primary origin in a disturbed
energetic balance (Deheeger et al 1996) and in PKU increased energy intake is usually recommend
in order to prevent catabolism (Illsinger et al 2005), that would have deleterious effects on metabolic
control (MacDonald et al 2006). From the available studies, energy intakes in PKU seems to match
the recommendations while carbohydrate ingestion is usually above 50% of the total energy intake
(Rocha et al 2013). A healthy diet usually promotes the consumption of food sources rich in complex,
fiber-rich carbohydrate sources. In PKU, there are not yet enough studies documenting in detail food
patterns. Anyway, it seems that carbohydrate sources used in PKU may have sometimes excessive
sugar content and may be low in fiber (Rocha et al 2013). Another crucial component of the typical
diet in patients with PKU is special low protein foods. These may have a contribution to the total
energy intake of around 50% in classical forms of the disease. So, it seems prudent to know in detail
all the nutritional composition of these foods, since their contribution will have a great influence in
nutritional status. It is important to know how different is their fat, sugar and energy contents
compared with general foods. Also, fiber, sodium and other micronutrients should be checked.
Nutritional status management in PKU is no longer just controlling Phe levels. We should aim for
optimizing global nutritional status since it will influence long-term outcome at several levels. On the
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other hand, fruits and vegetables are usually referred on the exchanges tables used in several treatment
centers. However, some studies already documented that free ingestion of fruits and vegetables may
not affect metabolic control in PKU (MacDonald et al 2003; Rohde et al 2012; Zimmermann et al
2012). This information should be used and translated into the clinical practice because it can result
in a good strategy for health promotion, considering the benefits of fruit and vegetable ingestion
(Koletzko et al 2013). Regarding protein, excessive ingestion in the first years of life should be
prevented, taking into account the known effects in terms of overweight development later in life
(Socha et al 2011). Considering the reduced protein content in human milk (Gillman 2008),
breastfeeding should be recommended in PKU (Motzfeldt et al 1999). The other component of the
protein intake in PKU is the protein substitutes, mainly composed by Phe-free amino acid mixtures.
The number of these has been increasing dramatically with different presentation forms, nutritional
composition and target ages. A careful analysis of their individual nutritional composition is needed
in order to better match them with individual patient’s needs.
Finally, but not less important, physical activity has a great influence on body weight and body
composition. However, there are no studies describing the physical activity behavior in patients with
PKU. The concept of diet for life, should also be adapted to the concept of treatment for life, since
nowadays other treatments are available for PKU patients. In that way, physical activity together with
a ‘balanced’ diet should be recommended in parallel with any other of the treatment strategies
proposed. Health care professionals have now the challenge to better define nutritional needs of each
patient in order to optimize both metabolic control but also long-term health outcome.
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