CLINICAL
THE MANAGEMENT OF CONGENITAL HYPERINSULINISM
Annaruby Cunjamalay Paediatric Dietitian Great Ormond Street Hospital for Children Annaruby is a highly specialised Paediatric Dietitian who has been working in paediatrics for 14 years. She has a keen interest in swimming and enjoys cooking and travelling the world.
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Congenital hyperinsulinism (CHI) is a rare but potentially serious condition that presents soon after birth. The estimated incidence is 1:40,000 births, with the highest incidence rate of 1:2500 births found in consanguineous parents.1 CHI is characterised by the over production of insulin secretion from pancreatic β-cells. The risk of brain injury results from insulin action stopping the body from using alternative fuels for the brain to use instead of glucose. It is, therefore, essential to make a rapid diagnosis and commence immediate management in order to prevent severe hypoglycaemic brain injury associated complications, such as epilepsy, cerebral palsy and other neurological damage, or even death.2 The aim of treatment is to avoid any episodes of hypoglycaemia. For the purpose of CHI, hypoglycaemia is less than 3.5mmol/litre. In the absence of ketone bodies, infants with CHI are constantly reliant on the circulating blood glucose as the fuel for normal neurological functioning, hence the importance of maintaining the blood glucose concentration above 3.5mmol/ litre. CHI is often missed, as it is difficult to identify, with non-specific symptoms such as abnormal feeding, irritability, jitteriness and lethargy. Despite advanced treatment, the evidence suggests that approximately a third of children with CHI have some degree of brain injury.3 Some of the neurodevelopmental problems are often only evident at school age when higher-order cognitive functions have developed; these children present with problems such as attention-deficit/hyperactivity disorders, plus learning problems.4
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Hypoglycaemic brain injury has a lifelong devastating effect on the child and the family, which consequently has a long-term socioeconomic impact on the NHS. WHAT ARE THE SYMPTOMS OF CHI?
A child usually starts to show symptoms within the first few days of life, although very occasionally symptoms may appear later in infancy. Symptoms of hypoglycaemia can include floppiness, shakiness, poor feeding and sleepiness, all of which are due to the low blood glucose levels. Seizures can also occur due to low blood glucose levels. If the child’s blood glucose level is not corrected, it can lead to loss of consciousness and potential brain injury. SECONDARY CAUSES OF HYPERINSULINISM
This can be subdivided into several categories and often distinguished by the length of treatment required and the infant’s response to medical management. Transient hyperinsulinaemic hypoglycaemia means that the increased insulin production is only present for a short duration and often resolves in the first few weeks or months of life and is found in conditions such as: • intrauterine growth retardation • infants of diabetic mothers • infants with perinatal asphyxia
This material is for healthcare professionals only.
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Figure 1: Focal and diffuse CHI - showing pancreas with focal lesion and diffuse disease
More research is needed to understand why transient hyperinsulinism occurs. Some syndromes present in the newborn period with hyperinsulinaemic hypoglycaemia. Up to 50% of infants with Beckwith-Wiedemann syndrome, an overgrowth syndrome, have been observed to develop hyperinsulinaemic hypoglycaemia.5 GENETICS
At present, there are seven known genetic causes of CHI, which can be inherited in an autosomal recessive or dominant manner. Abnormalities in the genes ABCC8 and KCNJ11 are the most common cause of severe CHI. Other rare causes are due to abnormalities in genes involved in regulating insulin secretion from the pancreas beta cells. Thus, testing for mutations in the ABCC8 and KCNJ1 and identification of parental origin is useful in assessing the likelihood of focal and diffuse hyperinsulinism (see Figure 1) early in the treatment. HISTOLOGY
There are two subtypes of CHI namely diffuse and focal. Focal lesions are usually small and a specific area of the pancreas is affected. Around 40 to 50% of infants with persistent CHI will have the focal form. Diffuse CHI affects the entire pancreas. It can be inherited in a recessive or dominant manner, or can occur sporadically. The management of diffuse and focal disease is different. Focal disease can now be cured and completely removed surgically if the lesions are located accurately. However, diffuse disease will require removal of almost the entire pancreas, a subtotal pancreatectomy (95%), but has a greater risk of long-term effects, such as diabetes or
pancreatic insufficiency. When this occurs, oral enzyme replacement therapy with meals is an option, but there is a chance of developing insulin dependent diabetes. Occasionally, hypoglycaemia can still occur after surgery for diffuse disease, but it is usually in a milder form, which is more responsive to medical management.6 HOW IS CHI DIAGNOSED?
This is usually done through detailed blood and urine tests taken while a child’s blood glucose level is low. If their blood glucose level does not fall sufficiently low during the initial period, they may have a diagnostic fast, where all fluids will be gradually reduced for a period of time until they become hypoglycaemic (3.0mmols/l or less for a very short period of time only). Once the diagnosis has been reached (or the fast has been completed), glucose is given intravenously through a drip or central venous device and/or a feed commenced to correct the blood glucose level back to normal. Once CHI is confirmed, treatment with medicines to stop insulin production is commenced. Blood samples are also sent for genetic analysis. The results of the genetic analysis helps in determining whether a child will need an 18-F-DOPA scan. 18-F-dopa Positron Emission Tomography (PET) A PET scan gives very detailed, threedimensional images of the body. It works by injecting an isotope called 18-F-DOPA. With this www.NHDmag.com March 2019 - Issue 142
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CLINICAL Table 1: Criteria for diagnosing CHI Serum glucose
<3.0mmol/l
Serum insulin
Detectable at the point of hypoglycaemia
C-peptide
Elevated at the point of hypoglycaemia
Free fatty acids
Low
Beta-hydroxybutyrate (ketones)
Nil
Ketones
None in the urine
Cortisol
May be low at the point of hypoglycaemia
Growth hormone
May be high
scan, doctors are able to identify the area of the pancreas from which excessive insulin is being produced. The treatment recommended by the doctors depends on the results of the scan.7 It is important to estimate the glucose requirements to maintain euglycaemia and increased requirements can be an important diagnostic step. A normal hepatic glucose production rate in a full-term newborn is 4-6mg/kg/minute, but in CHI, this figure can be much higher.8 The glucose infusion rate (GIR) is both helpful at diagnosis and a useful indicator of the severity of CHI throughout the acute management. Calculation of glucose requirements (GIR) for enteral feeds:8 Total CHO (g) x 100 (mg) ÷ weight (kg) ÷ 24 (hours) ÷ 60 (minutes) = mg/kg/min There are two specialist centres for CHI: Great Ormond Street Hospital, London (GOSH) in the South and a joint service between the Royal Manchester Children’s Hospital and Alder Hey Hospital in Liverpool in the North. These two centres in the UK have the expertise to carry out the detailed repeated blood glucose monitoring needed to deliver treatment. MEDICAL MANAGEMENT OF CHI
The aims of treatment are: to avoid any episodes of hypoglycaemia; to provide a safe tolerance to fasting that is age appropriate; to establish feeding; to ensure optimal growth and a good quality of life. The aim is to keep a child’s blood glucose level stable at 3.5mmol/litre to 10mmol/ litre. This can be managed by using formulas with added glucose polymers in feeds alongside medicines to reduce insulin secretion. 16
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Blood glucose monitoring The MDT will teach parents about blood glucose monitoring and medications prior to discharge. Parents are advised to monitor their children’s blood glucose prior to feeding and when unwell. Upon discharge, the medical team will ensure that every child is given an individualised hypo plan, in the event that a child develops hypoglycaemia. An emergency regime is also given and explained by the dietitian. This is made up from using a glucose polymer or SOS and is given to a child during periods of illness, or when the child is unable to eat/feed or drink as normal. When children with CHI are unwell, they are at a high risk of their blood glucose levels dropping very quickly. The emergency regime is designed to give an appropriate amount of CHO for the child’s age based on average nutritional requirements and used during illness, with the aim of preventing hypoglycaemia, allowing the child to be managed at home. DIETETIC INTERVENTION
Dietetic input can be difficult initially when a child is admitted to hospital. They are fluid restricted due to medication, or they need a high IV dextrose volume to maintain blood glucose. Thus, there is less fluid available for feeds and this can prevent oral feeding. If infants are unable to meet their nutritional requirements from enteral feeds for more than seven days, then parenteral nutrition (PN) alongside enteral feeds should be considered. Breastfeeding is promoted and well supported by the MDT. Whilst infants are fluid restricted, mothers can express breast milk, but latching
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CLINICAL Table 2: A summary of the drugs used in CHI Drug
Indications
Mechanism
Diazoxide
Hyperinsulinism
Opens KATP channels and - Fluid retention stabilises pancreatic beta cells - Rarely leucopenia and thrombocytopenia - Taste changes - Pulmonary hypertension echocardiogram recommended prior to commencement - Excessive hair growth
Chlorothiazide
Hyperinsulinism
Acts synergistically with diazoxide by activating non KATP channels
- Hyponatraemia - Hypokalaemia
Nifedipine
Hyperinsulinism
Inhibits voltage gated calcium channels in the B-cell membrane
- Hypotension
Sirolimus
Hyperinsulinism
Rapamycin (mTOR) inhibitor, beta cell suppressor
- Not used regularly within CHI due to its immunosuppressive side effects - Used in rare cases when other treatment options have failed
Glucagon
Hypoglycaemia
Increased glycogenolysis/ gluconeogenesis
- Nausea - Vomiting - Increased growth hormone - Increases myocardial contractility - Decreases gastric acid and pancreatic enzymes
Octreotide
Hyperinsulinism
Activates G protein-coupled rectifier K channel
- Suppression of growth hormones - Delayed gastric motility - Steatorrhoea - Cholelithiasis - Abdominal distention - Hepatitis - Hair loss
on after feeds, or in between for comfort, should be encouraged as soon as is safe. As these infants are fluid restricted, it can be effective to use a high energy feed to meet their energy, carbohydrate, protein and growth. Alternatively, a standard infant formula can be concentrated to meet their nutritional needs, but this should be monitored. Glucose polymers Infants with CHI will often require glucose polymers, such as Vitajoule or Maxijul, added to feeds to increase the carbohydrate concentration. Glucose polymers should be added in small increments to feeds, as this can cause an osmotic load and can predispose preterm babies to develop necrotising enterocolitis. It is important that each child is meeting a safe level of protein, based on 18
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Side effects/limitations
their age. When a glucose polymer is added to feeds, this can alter the protein-to-energy ratio and can have a negative effect on growth. The proteinto-energy ratio should between 7.5-12%.8 Tube feeding Children with CHI have feeding problems and are known to have food aversions.9 They have persistent feeding difficulties, with 75% requiring nasogastric (NG) tube feeding and 93% will require anti-reflux medications.10 Many infants will have NG tubes passed a number of times, causing facial/oral sensitivity and, hence, oral feeding experiences are affected. There are also side effects of medication, which can cause feeding difficulties. Other factors, such as excessive insulin production, affect gut dysmotility. Infants also suffer from gastro-
oesophageal reflux and are unable to tolerate large volumes of feed and so vomit. Studies have linked excessive insulin production with the suppression of the hormone ghrelin, which could explain why babies are disinterested in feeds.10 An NG tube is inserted to deliver continuous feeds. If tube feeding is required long term, a percutaneous endoscopic gastrostomy (PEG) is often needed. Even if a child has an NG tube or PEG, we encourage children to feed orally, as this is essential to maintain their oral motor skills, reducing the chance of long-term feeding problems. It is important that oral feeding is established as soon as possible. Assessment and support from speech and language therapists can help a child regain the desire to eat and drink by mouth. At discharge Infants are discharged on bolus feeding in the day and continuous feeding overnight to help maintain blood glucose levels. At the start of an overnight feed, a bolus feed is given and after an overnight feed too, as the blood glucose levels can drop quickly after continuous feeding. Prior to discharge, a unique feeding plan is devised for
the infant. Infants with CHI undergo a six-hour â&#x20AC;&#x2DC;safety fastâ&#x20AC;&#x2122; to ensure that they are safe to go home and maintain their blood glucose level. Normal weaning is encouraged at six months of age in line with the current DOH recommendations. A child with CHI may benefit from the use of uncooked cornstarch, a complex carbohydrate. This can be used to allow a longer fast period overnight. Uncooked cornstarch can help with blood glucose stability and slow digestion times, which range from four to nine hours. A 5g dose is recommended with a maximum 2g/kg/dose. This is not recommended in children under one year of age due to the immaturity of intestinal amylase.8 CONCLUSION
The management of CHI can be complicated. However, once infants with CHI are stable, a degree of normal life can be achieved. Brain function in CHI can be normal if hypoglycaemia has been diagnosed and treated quickly. This can be variable depending on the amount of damage caused before diagnosis and treatment. With increased knowledge and research, the outcomes for these children are continually improving.
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