CONDITIONS & DISORDERS
TYROSINAEMIA Tyrosinaemias are a group of inborn errors of metabolism requiring lifelong pharmacological and dietary treatment. The main objective of dietary therapy is to provide adequate nutrition allowing normal growth and development while controlling blood tyrosine levels. This article explains the dietary principles and management of tyrosine disorders. Dietary manipulation includes a protein-restricted diet and protein substitutes. Tyrosine (TYR) is one of the 20 standard amino acids present in the body and used by cells to synthesise proteins. TYR is considered a conditionally essential amino acid, derived from the hydroxylation of phenylalanine (Phe) and the hydrolysis 1,2 of dietary or endogenous protein. TYR is either used to form proteins or degraded to products such as fumarate and acetoacetate by the body. This step process is demonstrated by the tyrosine degradation pathway (see Figure 1 on our website: www.NHDmag.com/tyrresources.html). There are five acknowledged tyrosine disorders where dietary input is integral to management. Table 1 provides an overview of these, including classification, enzyme defect, clinical symptoms, biochemical findings and management. TYROSINAEMIA TYPE I (HT-1)
• Birth incidence of approximately 1 in 100,000. Quebec, Canada has the higher prevalence due to the founder effect.4 HT-1 is not formally screened for on initial newborn screening in the UK. • HT-1 occurs due to a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH) in the last step of the TYR degradation pathway (see Figure 1 online as before). • If HT-1 is not treated, toxins such as succinylacetone build up and
cause serious medical problems in the liver, kidneys and brain. • Clinical manifestations associated with HT-1 often vary greatly. Even when taking NTBC (2-[2-nitro4-trifluoromethylbenzoyl]-1, 3-cyclohexanedione), there are still important risks of longterm complications of HT-1, most importantly hepatocellular carcinoma. • Currently, liver transplantation is only considered in patients with acute liver failure (not responding to NTBC).5 • Pharmacological treatment NTBC (available since 19916) has greatly improved life expectancy. NTBC inhibits 4-hydroxyphenylpyruvate dioxygenase and prevents production of toxic metabolites below this enzyme step (FAA, MAA and SA) (see Figure 1 online as before). However, the drug does not prevent blood accumulation of TYR and Phe, therefore, dietary management is essential.7 DIETARY AIM OF TREATMENT
1 To optimise nutritional status. 2 To keep blood tyrosine levels within the recommended reference range (Table 2).
Harriet Churchill Specialist Dietitian National Hospital for Neurology and Neurosurgery. Harriet is working as a Specialist Dietitian at the Charles Dent Metabolic Unit, part of University College London Hospitals.
REFERENCES Please visit the Subscriber zone at NHDmag.com
To view Figure 1 and Table 3 related to this article, please visit www.NHDmag. com/tyr-resources. html).
DIETARY PRINCIPLES AND THEIR MANAGEMENT
Use of a protein substitute without Phe and TYR to provide sufficient protein, energy, vitamins and minerals The protein equivalent used needs to www.NHDmag.com June/July 2019 - Issue 145
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CONDITIONS & DISORDERS be Phe- and TYR-free, but complete in all the other amino acids to prevent catabolism and to contribute towards protein requirements. There is currently a limited range available, including amino-acid-based powders and ready-todrink options. Currently, there is not a tablet or glycomacropeptide (GMP) option available in the UK. GMP has been popular within the PKU population and GMP-based protein substitutes for tyrosinaemia have recently become available in limited flavours in other countries worldwide, in the USA for example. GMP-based products are commonly perceived to be more palatable than those based on amino acids and thus provide an alternative option.12,13 The energy content varies between products and contributes to daily intake. Protein substitutes also include micronutrients. A restricted protein diet results in lower intakes of micronutrients such as B12, zinc, calcium and iron, as well as essential fatty acids. Intakes should be guided by dietary reference values (vary for age and gender) and an individual’s biochemistry. Barriers and behaviours affecting compliance in HT-1 have been identified in observational reports, but this has received little rigorous study.12 Reported dietary challenges include consumption of supplements for a myriad of reasons (eg, for taste, palatability, bad breath, gastrointestinal symptoms), their frequency and volume required. All of which can affect long-term compliance. The supplements should also be taken throughout the day to optimise metabolic control. Restriction of natural protein to maintain plasma TYR and Phe in the goal range Food choices are an important consideration for individuals with HT-1 and they need to follow a tailored diet to limit their TYR intake. An exchange system is used with 1 exchange = 1g protein (or an assumed 50mg TYR). The amount of exchanges recommended varies on an individual basis due to tolerance variability (affected by age, gender, health, pregnancy and growth). The diet is tailored to provide individuals with enough Phe and TYR to keep blood levels in range, to prevent muscle catabolism and to meet nutritional 46
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requirements. Adjustment over time is likely to be required during growth and pregnancy, for example. Restricting high-protein foods is essential (eg, meat, fish, eggs, cheese, milk, nuts and seeds). Naturally-occurring low-protein foods, such as, fruit, vegetables, fats and sugars, should form the basis of the diet. Thorough lists of food examples13 are provided with exchange amounts and social media channels post newer products and ideas. Table 3 (on our website: www.NHDmag.com/tyr-resources.html) illustrates some examples of foods providing one exchange.14 Prescribable low-protein food products are available in order to support energy requirements (to prevent muscle breakdown raising TYR blood levels), to provide bulk in the diet to prevent hunger and, consequently, to prevent individuals eating unsuitable higher-protein foods, as well as to ensure the diet has variability. Examples of products available include bread, flour mixes, pastas and milk substitutes. Low-protein products are not available to purchase in the supermarket and we would expect ~50% of an individual’s energy intake to come from these prescribed products.15 MONITORING
Individuals should be under the care of a metabolic team long term, to ensure metabolic and dietary aims are monitored. Adult monitoring varies depending on the individual’s engagement. Management recommendations for HT-1 were published in 2013,3 which include long-term and clinic follow-up recommendations as follows: • Ensure NTBC is dosed correctly and good compliance, essential to prevent serious complications, including acute liver failure and a neurological crisis.14 • Regular liver imaging every six months. • Regular clinic bloods, including amino acid profile, full blood count, liver function tests, urea and electrolytes, NTBC, as well as nutritional markers due to restricted diets, such as Iron, ferritin, vitamins A, B12, D, E, folate, selenium, zinc and copper.
CONDITIONS & DISORDERS Table 1: Overview of tyrosine disorders2 Disorder
Enzyme defect
Clinical symptoms (if unmanaged)
Biochemical
Management
Tyrosinaemia type I (HT-1)
Fumarylacetoacetate hydrolase (FAH)
Severe liver failure, vomiting, bleeding, neuropathy, neurological crises, cirrhosis, hepatocarcinoma
↑urine and blood succinylacetone (diagnostic), ↑TYR, ↑MET (when liver disease has progressed)
Nitisinone (NTBC); Phe- and TYRrestricted diet (liver transplantation for select patients)
Tyrosinaemia type II
Tyrosine aminotransferase (TAT)
Corneal lesions, hyperkeratosis, neurological complications
↑↑TYR (blood and urine), ↑increased Phe, ↑urinary phenolic acids
Phe- and TYRrestricted diet
Tyrosinaemia type III and neonatal tyrosinaemia
4-hydroxyphenylpyruvic acid dioxy-genase (4-HPPD)
Impaired mental function, uncertain clinical relevance
↑TYR, ↑urinary 4-HPPA
Phe- and TYRrestricted diet; short term protein restriction in neonatal tyrosinaemia
Hawkinsinuria
4-hydroxyphenylpyruvic acid dioxy-genase (4HPPS); autosomal dominant mutation
Failure to thrive, acidosis, doubtful clinical relevance
↑urinary hawkinsin acetic acid (2-L-cysteineS-yl, 4-dihydroxycyclohex- 5-en-1-yl)
Phe- and TYRrestricted diet + vit C supplementation in infancy
Alkaptonuria
Homogentisate oxygenase (HGD)
Arthritis, cardiac valve disease
↑homogentisic acid
Low-protein diet, possibly NTBC
Table 2: Target blood TYR and Phe levels Amino acid
Recommended plasma TYR level
Unaffected adult
30-120μmol/L8
HT-1
200-400μmol/L3
• Psychometric baseline assessment and eye examination recommended. • Bone mineral density monitoring suggested due to restricted diet. • Dietary review to supervise necessary Phe and TYR restrictions. • We also offer individuals home monitoring between clinic visits through sending bloodspots in for Phe and TYR. Challenges faced with dietary monitoring • Recommendations include dietary restrictions to be continued indefinitely and should be carefully supervised – this relies on individuals engaging, attending
Recommended plasma Phe level
50-100μmol/L8,9
appointments and motivation. • Strict metabolic control to maintain tyrosine concentrations 200-400μmol/l is recommended until age 12; however, the safety of slightly increased concentrations is unknown, as well as increased levels when >12 years old.3 Keeping levels within target range can be challenging for individuals. Long-term follow-up studies to review target plasma concentrations of TYR and Phe are needed.3 • Raised CSF concentrations of TYR are associated with raised plasma TYR concentrations. The effects on the tryptophanderived neurotransmitters are not known.16 www.NHDmag.com June/July 2019 - Issue 145
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CONDITIONS & DISORDERS • Low Phe concentrations may be damaging; if persistent, Phe supplements may be used to prevent catabolism and raised TYR levels. Diurnal variation of plasma levels is reported, so timing of any supplements should be considered and additional Phe
supplements may increase plasma TYR concentrations.17 • If poor dietary compliance occurs, micronutrients may be deranged and additional supplementation needed, requiring further adherence.
CASE STUDY EXAMPLE Background Divya has HT-1 which was diagnosed at age five. She is currently 25 years old, without children and works in IT. Her medical history only includes HT-1. Divya’s diet is: • low protein (not usually counting exchanges, but reports about 18); • prescribed protein substitute three times daily with poor adherence. Her TYR levels are usually between 600-900umol/L. Issues • Poor engagement with metabolic team. • Longstanding difficulty of taking NTBC and protein substitutes resulting in a recent neurological decompensation. • Divya’s diet became nutritionally inadequate since she was still following a low-protein diet without taking her protein substitutes. • Divya has limited menu options. • Prolonged hospital admission including rehabilitation. Low-protein diet with variability and tailored menus due to duration of admission, requiring enteral nutrition and transition back to oral intake and increase in exchanges as blood levels improved. The role of the dietitian • To promote nutritional status and minimise nutritional losses during recovery and rehabilitation. This included education from the multidisciplinary team about HT-1 and its management. • To collaborate with Divya to promote motivation and engagement with the restricted diet. • To work together to provide practical ways to follow the diet. • To educate through practical cookery sessions on how to follow the restricted diet and menu planning sessions for ideas. • To collaborate with psychological colleagues to try techniques to promote behaviour change to protein substitutes. Outcome for Divya • Divya is now discharged from her admission. • She reported taking her NTBC about three times per week which puts her at high risk of further neurological decompensation. • She is receiving ongoing psychiatry input for her aversion to protein substitutes and remains taking minimal, if any, per day. She is encouraged to take a multivitamin due to poor compliance. • She has so far attended her scheduled follow-up appointments, but blood TYR levels remain above target range. • Divya remains on a relatively low-protein diet, as she is not taking her substitutes, however, she is unlikely to meet her nutritional requirements, therefore, remaining at high risk of micronutrient deficiencies and requiring bone mineral density scanning. CONCLUSION
Dietary treatment remains integral to the overall management of HT-1. Adherence to and engagement with dietary and pharmacological treatment is critical to reduce the risk of complications, such 48
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as, neurological decompensation and hepatic complications. HT-1 has a limited evidence base and a low incidence. However, it is clear that good outcomes involve regular monitoring and compliance with lifelong management.