NHD CPD eArticle Vol: 8.01 by NH Publishing Ltd

NHD CPD eArticle NETWORK HEALTH DIGEST

Volume 8.01 - 18th January 2018

NEW GALACTOSAEMIA GUIDELINES: WHAT DO THEY MEAN FOR DIETITIANS? Pat Portnoi Dietitian to the Galactosaemia Support Group (GSG) Pat has worked for the GSG for 19 years. For many years, Pat and Anita have undertaken research on cheese in galactosaemia and have recently been involved in developing the new international guidelines on galactosaemia.

Anita MacDonald Consultant Dietitian in Inherited Metabolic Disorders, Birmingham Children’s Hospital Anita has had 38 years of clinical experience in Paediatric Dietetics, particularly Inherited Metabolic Disorders. She is a highly respected researcher, writer and teacher in IMD Dietetics. Anita is particularly interested in galactosaemia and PKU.

Galactosaemia is an inherited inborn error of carbohydrate metabolism, affecting one in 44,000 people in the UK. It is more common in the Irish and traveller populations. Although specialist dietitians in metabolic centres are in the best position to take care of their dietary needs, many patients with galactosaemia receive their routine care at district general hospitals. Galactosaemia is caused by a profound deficiency of galactose-1-phosphateuridyltransferase, which leads to the accumulation of various metabolites. Fundamentally, it is managed by a lifelong, very low lactose/galactose diet. Although the disorder has been treated for 60 years, patient outcome is variable, but with many having cognitive, executive and neurological dysfunction. There is no apparent relationship between severity of dietary restriction and patient outcome.1 The actual cause of long-term clinical problems is not established. In 1999, the UK Galactosaemia Steering Group published national guidelines for the UK, but there was no formal assessment of the evidence.2 No other guidelines had been published at that time. In 2012, a review of current practice of management showed that treatment practice varied widely.1 A dietetic review of the severity of galactose restriction in adults in Europe, Australia and New Zealand3 also indicated diverse clinical practice. HOW THE GALACTOSAEMIA GUIDELINES WERE DEVELOPED

To provide patients around the world with the same state-of-the-art care, evidence-based guidelines were devel-

oped by the Galactosaemia Network (GalNet), and 23 international experts in their own fields from Europe and the USA working together. Ten different fields of interest in classical galactosaemia were identified: 1) Diagnostics 2) Biochemical follow-up 3) Dietary management 4) Cognitive development 5) Speech and language development 6) Neurological complications 7) Psychosocial development and mental health 8) Endocrinology and fertility 9) Bone health 10) Ophthalmological complications Key questions were suggested for each area of interest. Formalised literature searches were undertaken for each key question and selected published studies were evaluated by each subgroup. Consensus was reached within each group and recommendations developed accordingly. The body of evidence for each recommendation was ‘low to very low’ because of the rarity of the disorder and difficulties in performing randomised controlled trials when patient numbers are

Copyright © 2018 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 limited. Accordingly, each recommendation was assigned a strength of recommendation. Only if highly consistent results were found across multiple studies was it considered strong (++). Discretionary recommendation (+) was for those recommendations based on ‘expert opinion’ or with a low body of evidence. RECOMMENDATIONS

Forty recommendations were developed in total and recommendations 4 to 7 are of particular interest to dietitians. The new international guidelines were published in 2016.12 The following questions were posed to the nutrition and dietetic subgroup: • What is the safe amount of dietary galactose (for the different age groups)? • Based on the answer to the above question: should fruit/vegetables/mature cheese/ offal/legumes be restricted in the diet? • Should the diet be evaluated regularly for deficiencies? Which deficiencies and how frequently? Recommendation 4 (++) Clinicians should immediately commence a galactoserestricted diet (e.g. soy-based, casein hydrolysate or elemental formula) if classical galactosaemia is suspected in an infant, without waiting for confirmation of the diagnosis. In the UK, there has been debate over the inclusion of infant soya formula in galactosaemia, due to the concerns about its mild oestrogenicity. The 2013 UK COT report suggested that there should be no requirement to use soy-based infant formula in the UK, and proposed that alternative infant formulae be used. In 2014, a review and meta-analysis demonstrated no effects on long-term growth, bone health and metabolic, reproductive, endocrine, immune and neurological functions, and neurocognitive parameters in children without galactosaemia treated with soy-based formula.4 Soya formula remains the product of choice in the UK. Amino acid formula containing L-amino acids may be used, although these are more expensive and there is no obvious benefit to those infants using these formulae. Caseinbased formulae derived from milk casein are also used, but they do contain traces of residual

Volume 8.01 - 18th January 2018

lactose (<10mg/100ml). Whey-based formulae are not suitable. All clinics eliminate all animal milks from the diet.1,3 Recommendation 5 (expert opinion, +) We recommend treating patients with classical galactosaemia with a life-long galactose-restricted diet that only eliminates sources of lactose and galactose from dairy products, but permits galactose from nonmilk sources that contribute minimal dietary galactose. Within this definition, we accept that small amounts of galactose are present in specific mature cheeses and caseinates. At present, there is insufficient evidence to support a specific age-related recommendation of the quantity of galactose allowed in the diet. Recommendation 6 (+) We recommend allowing any amount and type of fruits, vegetables, legumes, unfermented soy-based products, mature cheeses (with galactose content <25mg/100g), and the food additives sodium or calcium caseinate, in the diet for classical galactosaemia. Although higher in galactose, all fermented soy-based products can be allowed in the small quantities that are typically used in the diet. The opinion about whether to restrict offal in the diet is divided; its galactose content is unknown, but there is no direct evidence of harm. It is a theoretical risk only, therefore it has been decided to put offal in the ‘in moderation’ section in the ‘Current diet restriction for Classical Galactosaemia’ table. In the UK, there has been a long-term policy of allowing all fruit, vegetables and legumes in the diet and so this recommendation is not altered. There is no evidence that this level of dietary galactose has any adverse effects on long-term clinical status. In fact, other countries are now adopting this dietary approach, after further analysis and review of the galactose content of fruit vegetables and legumes.5 The galactose intake from these sources is mostly less than 50mg/100g amounting to an estimated 54mg/day.6 This galactose intake is negligible compared to the endogenous galactose production in humans, which is thought to contribute to development of long-term complications. The endogenous production of galactose is highest in the newborns (>24.8mg/ kg/day) and falls to a minimum of 8.4mg/kg / day in adults.11

Figure 1: Cheese allowed and not allowed in Galactosaemia

Cheese in GalactosaemiaSUMMARY

• • • • • •

•

ALLOWED Emmental Gruyere Comte Jarlsberg All UK extra mature and vintage cheddar Italian Parmesan/ Grana Padano Vegan cheese

Mature hard cheese contains a low or negligible galactose content, and has been allowed in the UK since 2000. Based on experience, the amount of galactose allowed from cheese has now relaxed slightly to <25mg/100g. Cheese is a good source of calcium and other nutrients and helps to give variety to the diet. Recent analysis of extra mature and vintage cheddar in the UK means that these types of cheese are now allowed. Extra mature cheddar (typically 12-15 months in age) and vintage cheddar (typically 15-18 months or more) from supermarkets and traditional farms were analysed and found to be suitable for use in galactosaemia. A list of suitable cheese in the UK is given in Figure 1. Low lactose milk, cheese and products are not allowed in galactosaemia. Lactose has been hydrolysed to glucose and galactose. Some may have been filtered ‘out’ but considerable galactose remains, even if the lactose content is low. Offal has not been restricted in the UK for many years, whilst it has been restricted in other countries. The decision to allow it in moderation in the recommendations does not affect UK practice, and there is no evidence to show that outcomes from the UK (where offal is allowed) are any different from other countries where it

• • • •

• • •

NOT ALLOWED Soft cheese Young or mild Cheese Cheese spread Manufactured cheese dishes Brie, Wensleydale, Stilton All other cheddar Lactofree cheese

is not. There is very little evidence to date on the galactose content of offal. Caseinates have been restricted in the UK, but in practice, these are very low in galactose. Therefore, caseinates used as additives are now allowed in the UK. In practice, most food labels identify only milk, milk powder or skimmed milk powder on the label rather than individual proteins such as casein or whey. The addition of caseinates will make little difference to the quality or variety allowed in the diet. There is a continuing debate about possible dietary relaxation with increasing age, but no definite recommendation can be given. There is concern that an overly strict galactose restriction may be harmful.7 Short-term studies have indicated that intakes of oral galactose in adults and adolescents of 4,000mg galactose over 14 weeks had no effect on RBC Gal-1-P concentrations and no clinical manifestations were observed in this time frame. Overall experience is limited and there is insufficient evidence to support discontinuation of a galactose restricted diet. However, two case studies were reported of adults who were homozygous for Q188R and were ingesting 2,500 and 9,000mg galactose per day respectively, and whose outcome was comparable to those seen in treated adults.8,9

NHD CPD eArticle Recommendation 7 (+) We recommend an annual assessment of calcium and vitamin D intake with measurement of OH-vitamin D levels. Both calcium and vitamin D should be supplemented as necessary, following the age-specific recommendations for the general population. Patients with galactosaemia are at risk of calcium and vitamin D deficiency because of cows’ milk avoidance. It is thus important to regularly monitor the intake of nutrients associated with bone health. High calcium foods should be encouraged with milk replacements enriched with calcium and vitamin D. Vitamin D is necessary for calcium absorption and its biochemical status requires monitoring. In addition, a good balanced diet is generally important for bone health with plenty of fruit and vegetables. BONE HEALTH

There was a recommendation that bone mineral density screening, e.g. DXA, should be undertaken regularly according to current bone health guidelines. A follow-up DXA scan is recommended every five years with appropriate treatment accordingly. BLOOD TESTS

Monitoring of blood biochemistry is an area of some uncertainty. There are doubts about the ability of red blood cell Gal-1-P to monitor quality of control and dietary adherence. There is little association between galactose metabolites and long-term complications. The new guidelines

Volume 8.01 - 18th January 2018

suggest measuring red blood cell Gal-1-P at diagnosis and after three and nine months on a galactose restricted diet. They stabilise at an individual level that is usually higher than in the general population. After the first year of life, red blood cell Gal-1-P should be measured annually until an individual baseline has been achieved. Further monitoring of red blood cell Gal-1-P is only recommended if there is a concern over increased galactose intake and intoxication. CONCLUSIONS

There is much further information on how to manage fertility and many of the learning problems and neurological complications that are seen in galactosaemia. The guidelines are published in the Journal of Inherited Metabolic Disease (JIMD) as a short report highlighting the actual recommendations.10 However, the long paper is very informative and gives a rounded background to the many areas of uncertainty, and also explains how the recommendations were established. The recommendations and guidelines are the first international evidenced-based guidelines for diagnosis, treatment and follow-up of galactosaemia. There is limited information at present and there are many areas where additional information and evidence is needed. However, in the UK, the current dietetic management strategies are broadly in line with the guidelines and dietitians should be aware of the small but important changes highlighted.

References 1 Jumbo-Lucioni PP, Garber K, Kiel J et al (2012). Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes. J Inherit Metab Dis 35:1037-49. doi: 10.1007/s10545-012-9477-y 2 Walter JH, Collins JE, Leonard J V (1999). Recommendations for the management of galactosaemia. UK Galactosaemia Steering Group. Arch Dis Child 80:93-6 3 Adam S, Akroyd R, Bernabei S et al (2015). How strict is galactose restriction in adults with galactosaemia? International practice. Mol Genet Metab 115:23-6. doi: 10.1016/j.ymgme.2015.03.008 4 Vandenplas Y, Castrellon PG, Rivas R et al (2014). Safety of soya-based infant formulas in children. Br J Nutr 111:1340–60. doi: 10.1017/S0007114513003942 5 Van Calcar SC, Bernstein LE, Rohr FJ et al (2014). A re-evaluation of life-long severe galactose restriction for the nutrition management of classic galactosemia. Mol Genet Metab 112:191-197. doi: 10.1016/j.ymgme.2014.04.004 6 Berry GT, Palmieri M, Gross KC et al (1993). The effect of dietary fruits and vegetables on urinary galactitol excretion in galactose-1-phosphate uridyltransferase deficiency. J Inherit Metab Dis 16:91-100 7 Coss KP, Byrne JC, Coman DJ et al (2012). IgG N-glycans as potential biomarkers for determining galactose tolerance in Classical Galactosaemia. Mol Genet Metab 105:212-220. doi: 10.1016/j.ymgme.2011.10.018 8 Lee PJ, Lilburn M, Wendel U, Schadewaldt P (2003). A woman with untreated galactosaemia. Lancet 362:446 9 Panis B, Bakker JA, Sels JPJE et al (2006a). Untreated classical galactosemia patient with mild phenotype. Mol Genet Metab 89:277-279. doi: 10.1016/j. ymgme.2006.03.002 10 Portnoi PA, MacDonald A (2015). The Lactose and Galactose Content of Cheese Suitable for Galactosaemia: New Analysis. JIMD Rep. doi: 10.1007/8904_2015_520 11 Schadewaldt P, Kamalanathan L, Hammen HW, Wendel U (2004). Age dependence of endogenous galactose formation in Q188R homozygous galactosemic patients. Mol Genet Metab 81:31-44. doi: 10.1016/j.ymgme.2003.10.007 12 Welling L et al (2016). International clinical guideline for the management of classical galactosaemia: diagnosis, treatment and follow-up JIMD ( doi:10.10007/ s10545-0169990-5 Copyright © 2018 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 8.01 - 18th January 2018

Questions relating to: New galactosaemia guidelines: What do they mean for dietitians? Type your answers below, download and save or print for your records, or print and complete by hand. Q.1

Describe the aetiology of galactosaemia.

Q.2

What is the immediate dietary recommendation if galactosaemia is suspected?

Q.3

Explain the issues surrounding soy-based infant formula as part of a galactose-restricted diet.

Q.4

What is the recommendation on allowing all fruit, vegetables and legumes in the diet of galactosaemia patients?

Q.5

Describe the recommendations for cheese and cheese products in the galactose-restricted diet.

Q.6

Outline the debate surrounding dietary relaxation with increasing age.

Q.7

Why should calcium and vitamin D be supplemented in galactosaemia patients?

Q.8

What are the recommendations for ongoing monitoring of galactosaemia?

Please type additional notes here . . .

Copyright ÂŠ 2018 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.