Metabolic Medicine clinical outcomes

Clinical outcomes are measurable changes in health, function or quality of life that result from our care. Constant review of our clinical outcomes establishes standards against which to continuously improve all aspects of our practice.

Great Ormond Street Hospital’s (GOSH) service is the largest paediatric metabolic centre in the UK. We are the principal provider of specialist child metabolic medicine services for London (north of the Thames) and the surrounding counties, and we provide a national and international service for the management of rare and complex paediatric metabolic conditions.

We see patients from 0 to 16 years old with suspected or diagnosed metabolic disease, including disorders of intermediary metabolism, neurometabolic disorders, congenital disorders of glycosylation (CDG), disorders detected on newborn screening, galactosaemia, familial hypercholesterolaemia (FH) and mitochondrial disorders. We are one of three nationally-commissioned NHS specialised services for the management of children with lysosomal storage disorders (LSD).

The Clinical Biochemistry department at GOSH is one of the UK newborn screening centres. The Metabolic Medicine Service provides care for all neonates from our catchment area with positive neonatal screening results, which include phenylketonuria (PKU), medium-chain acyl-CoA dehydrogenase deficiency (MCADD), glutaric aciduria type 1 (GA1), isovaleric acidaemia (IVA), maple syrup urine disease (MSUD) and homocystinuria (HCU).

Our multi-disciplinary metabolic team is comprised of consultants and clinical nurse specialists, with specialist input from metabolic dieticians, biomedical scientists, physiotherapists, clinical psychologists, social workers, and speech and language therapists.

LSD is an umbrella term for a group of more than 50 genetic disorders that are caused by a lysosomal enzyme deficiency. Worldwide, these conditions affect an estimated one in 7,700 people.

Many of the LSDs display a progressive disease pattern, which means that symptoms get worse over time if left untreated. Treatments for some of the LSDs include enzyme replacement therapy (ERT), which is administered intravenously every week or two, depending on the type of disorder.

It is important for the wellbeing of the child and their family to seek, where possible, to reduce disruption caused by the treatment frequency. Home infusion can help, with fewer days of school missed, less disruption for parents and siblings, and reduced travel and financial implications.

Home infusion can only be an option if it can be established safely with patient/family training, with protocols in case of infusion reactions, and with support from the specialist centre.

Table 1.1 Number of children with an LSD on home ERT

Of 82 current GOSH patients (as at March 2019), for whom homecare is suitable, all 82 (100 per cent) are on home ERT.

Table 1.2 Number of children with an LSD on ERT who are transferred within three months of commencement of therapy

For 2018/19, 4 (100%) of children were transferred to home ERT within three months of commencement of therapy.

For April 2015 to March 2019, 21 (72%) children were transferred to home ERT within three months of commencement of therapy. Eight (28%) of children were transferred after three months because they had severe infusion reactions and were kept longer in order to get them on pre-infusion medication that stopped the reactions.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare inherited genetic disorder in which there is a block in the metabolism of fat into energy when the body's demand for energy increases and calorie intake is often reduced. This means that when someone with MCADD develops an illness, such as diarrhoea and vomiting or an infection that prevents them eating, they are at risk of becoming more unwell, and they are also at risk of developing hypoglycaemia.

MCADD is a lifelong condition that is present from birth. It is estimated to affect up to 1 in every 8,000 babies born in the UK and is usually picked up using the newborn blood spot test. Medical complications of the condition can usually be prevented, so early detection and medical management is very important.

Newly identified patients with MCADD should be seen for a 'face-to-face review' within 24 hours of receiving information about the newborn screening result. At the review, they are provided with necessary information and an emergency regimen, which is a special feeding plan to provide patients with energy if they are unwell or unable to take their normal nutritional intake.

Numerator: The number of newly identified MCADD Newborn Screening (NBS) patients seen for a 'face-to-face review ' by the metabolic clinical team within 24 hours of receiving the screening report and provided with necessary information and emergency regimen.

Denominator: Total number of new positive diagnoses of MCADD by NBS at the centre.

Table 2.1 Number of MCADD patients seen for a review within 24 hours

This measure is a national measure that is reported to commissioners by MCADD specialised services. Between April 2017 and March 2019, all patients received clinically appropriate care and were provided with the necessary information and an emergency regimen. As per national protocol, we see patients on the next working day after diagnosis. Therefore, a small number of patients who were diagnosed on the weekend were seen on the next working day, rather than ‘within 24 hours’. One patient was admitted to another hospital and was seen at GOSH once clinically stable. For clinically appropriate reasons one patient was not seen ‘face-to-face’, though the treatment and information were provided at birth, before newborn screening. This patient was subsequently seen at GOSH for a review. One patient referred to GOSH more than 6 months after birth was seen on the day of referral.

Children and young people with metabolic conditions will often need to follow an emergency regimen diet when they become ill (such as vomiting or diarrhoea) to help prevent deterioration of metabolic function and a possible admission to hospital. This involves drinking a special high glucose drink at specific times until they are able to resume their regular diet. This is particularly important for those with a group of conditions called organic acidaemias.

A measure of our effectiveness that we report to NHS England each year is the number of patients with propionic acidaemia (PA) or methylmalonic acidaemia (MMA) that is non-Vitamin B12 responsive, who have an emergency regimen as per the British Inherited Metabolic Disease Group guidelines (www.bimdg.org.uk).

Figure 3.1 Percentage of patients with PA or MMA (non-vitamin B12 responsive) provided with an emergency regimen

These results show that 100% of our children and young people with these conditions are provided with an emergency regimen. This means that parents/carers are able to promptly implement the appropriate emergency regimen at home at the start of any illness that disrupts their child’s regular diet. This helps to avoid the co-occurrence of potentially serious metabolic problems when their child is unwell.

To ensure that the emergency regimen is up-to-date for each patient, the regimen should also be reviewed at least yearly and adjusted accordingly.

This measure shows the number of children and young people with PA or MMA (non-vitamin B12 responsive) whose emergency regimen has been reviewed within 12 months. To ensure relevance of the data, patients who moved countries, transitioned to adult health services or died prior to their review date are not included in the figures.

Figure 3.2 Percentage of patients with PA or MMA (non-vitamin B12 responsive) with an appropriate emergency regimen, reviewed at least yearly

Our results show that we have a near 100% achievement of yearly review of emergency regimens for our children and young people with PA or MMA (non-vitamin B12 responsive). This means that if they do become unwell, they can be given an up-to-date emergency regimen diet that is most appropriate for their age and weight to support their metabolic function during sickness.

Familial hypercholesterolaemia (FH) is an inherited condition characterised by high levels of LDL-cholesterol. It results from mutations in genes affecting cholesterol metabolism. High cholesterol levels lead to atherosclerotic plaque deposition in the blood vessels causing premature coronary heart disease. With the right treatment the onset and severity of symptoms can be delayed. Diagnosis is based on the use of diagnostic criteria and there are currently three formal diagnostic criteria for FH widely used in Western countries. The identification of a pathogenic variant in a gene known to be associated with FH is nevertheless the gold standard for diagnosis. Published guidelines from the National Institute for Health and Care Excellence includes the standard, ‘Healthcare professionals should offer people with a clinical diagnosis of FH a DNA test to increase the certainty of their diagnosis and to aid diagnosis among their relatives.’

Here at GOSH, we follow this standard and we measure our performance against it to ensure that we perform DNA testing as part of the care we provide to our patients and their families. To standardise our approach to clinical diagnosis for this measure, we use the Simon Broome criteria as our first screen method for establishing a clinical diagnosis of FH.

The greater the number of patients with possible FH whose diagnosis is confirmed through DNA testing:

• the more we can work with pro-actively to postpone any effects of the condition upon the cardiovascular system
• the greater the number of families we can work with to aid diagnosis among family members

Table 4.1 Patients with possible FH who are DNA tested, 2017/18

The table above shows that for 2017/18, 28 patients met the Simon Broome criteria for a clinical diagnosis of FH. All of them were DNA tested. Out of the patients who had DNA testing, 21 (75%) were genetically confirmed to have FH. This is in accordance with results from literature stating that genetic confirmation is accomplished in 70-95% of patients by testing for mutations in the most common genes affecting cholesterol metabolism.

We have additionally performed DNA testing on 11 patients with high cholesterol levels but who did not meet the Simon Broome criteria. Seven patients from that group were genetically confirmed as well, showing that criteria are helpful, but must be used in conjunction with clinical judgement to avoid missing FH confirmations. Genetic results have been communicated to the family and local doctors/GPs in order to proceed to further family member screening.

Phenylketonuria (PKU) is one of the conditions screened for in the national newborn blood spot screening programme. PKU is an inherited metabolic condition in which phenylalanine (an amino acid and therefore a component of protein) cannot be broken down. It results in elevated levels of phenylalanine in the blood. Left untreated, PKU causes brain damage and neuro-developmental delay. However, with early management patients can achieve normal development.

Treatment for PKU is a very low protein diet with a special phenylalanine-free or low phenylalanine protein substitute.

The amount of protein that can be eaten varies on an individual basis. Dietary management is guided by regular blood phenylalanine monitoring. The frequency of blood spot monitoring varies depending on age and individual. Generally blood spots are taken weekly in infants under 6 months, fortnightly in infants and children aged 6 months to 4 years and then monthly thereafter.

European guidelines for management of PKU were updated in 20171. In these guidelines, the target blood phenylalanine concentrations when on treatment are:

• 0 to 11 years: 120 – 360 µmol/L
• 12 years and above: 120 – 600 µmol/L

Prior to 2017 target phenylalanine levels were

2

:The median phenylalanine concentration from blood spot monitoring for all our children and young people with PKU attending clinics at GOSH from April 2018 – March 2019 were calculated.

• 0 to 12 years: 120 – 360 µmol/L
• greater than 5 years: 120 – 480 µmol/L
• greater than 10 years: 120 – 480 µmol/L but could accept 120 – 700 µmol/L 

The mean of the medians for children aged 0 to 11 years is 365 µmol/L.

The mean of the medians for young people aged 12 to 17 years is 553 µmol/L.

Figure 5.1 summarises the proportion of children aged 0 to 11 years with median phenylalanine concentrations in range (120 – 360 µmol/L). The median phenylalanine is within range for 63% (65/104) of children aged 0 to 11 years.

Figure 5.1 Proportion of median phenylalanine levels in range for children aged 0 to 11 years

Figure 5.2 summarises the proportion of young people aged 12 to 17 years with median phenylalanine levels in range (120 – 600 µmol/L). The median phenylalanine concentration is within target range for 66% (44/67) of young people aged 12 to 17 years.

Figure 5.2 Proportion of median phenylalanine levels in range for young people aged 12 to 17 years

Figures 5.3 and 5.4 summarise the mean of the median phenylalanine concentrations at each year of age. The dotted line marks the upper limit of the target treatment range1.

Figure 5.3 Mean of the median phenylalanine concentrations at each year of age (0 to 11 years)

Figure 5.4 Mean of the median phenylalanine concentrations at each year of age (12 to 17 years)

The mean of the median phenylalanine concentrations in children aged 7, 8, 9, 10 and 11 and young people aged 16 and 17 years are above the current European guideline targets1. However, median phenylalanine concentrations would have been within range when following previous consensus targets prior to 20172.

Blood phenylalanine concentrations can become elevated due to illnesses such as a fever or vomiting, insufficient intake of phenylalanine-free, or low phenylalanine protein substitute or excessive consumption of dietary phenylalanine (protein). Conversely, blood phenylalanine concentrations may fall due to periods of accelerated growth, insufficient intake of phenylalanine-free or low phenylalanine protein substitute. Any of these reasons may explain the incidence of blood phenylalanine concentrations that are not in range. GOSH is committed to working with and supporting children, young people and their families to achieve optimal blood phenylalanine levels, particularly as we transition to meet new European guideline targets.

We also value the opportunity to contribute to research that furthers the understanding and management of this condition around the world.

1 van Spronsen FJ, et. al, Key European guidelines for the diagnosis and management of patients with phenylketonuria, The Lancet Diabetes & Endocrinology, 2017 Sep;5(9):743-756, doi: 10.1016/S2213-8587(16)30320-5, Epub 2017 Jan 10

2 The National Society for Phenylketonuria UK (NSPKU), Management of PKU, Second edition April 1999

This information was published in December 2019.