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Persistent hyperinsulinaemic hypoglycaemia in infancy
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Persistent Hyperinsulinaemic Hypoglycaemia in infancy Pratik Shah, Huseyin Demirbilek, Khalid Hussain
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Seminars in Pediatric Surgery
Cite this article as: Pratik Shah, Huseyin Demirbilek, Khalid Hussain, Persistent Hyperinsulinaemic Hypoglycaemia in infancy, Seminars in Pediatric Surgery, http: //dx.doi.org/10.1053/j.sempedsurg.2014.03.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Persistent Hyperinsulinaemic Hypoglycaemia in infancy Pratik Shah1, Huseyin Demirbilek 1, Khalid Hussain1 1
Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit,
Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH & Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London WC1N 3JH Corresponding author Dr. K. Hussain Developmental Endocrinology Research Group Clinical and Molecular Genetics Unit Institute of Child Health University College London, 30 Guilford Street, London WC1N 1EH Tel: ++44 (0)20 7 905 2128 Fax: ++44 (0)20 7 404 6191 Email: [email protected]
Key Words: Hyperinsulinaemic hypoglycaemia, diffuse, focal, Word Count: Abstract: 220 Manuscript: 3600
Abstract Context: Persistent Hyperinsulinaemic Hypoglycaemia in Infancy (PHHI) is a heterogeneous condition characterised by unregulated insulin secretion in response to a low blood glucose level. It is the most common cause of severe and persistent hypoglycaemia in neonates. It is extremely important to recognise this condition early and institute appropriate management to prevent significant brain injury leading to complications like epilepsy, cerebral palsy and neurological impairment. Histologically, PHHI is divided mainly into three types - diffuse, focal and atypical disease. 18F-DOPA-PET/CT (Fluorine-18-L-3,4-dihydroxyphenylalanine positron emission tomography) scan allows differentiation between diffuse and focal disease. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localised to a small region of the pancreas. The molecular basis of PHHI involves defects in key genes (ABCC8, KCNJ11, GCK, SLC16A1, HADH, UCP2, HNF4A and GLUD1) which regulate insulin secretion. Focal lesions are cured by lesionectomy whereas diffuse disease (unresponsive to medical therapy) will require a near total pancreatectomy with a risk of developing diabetes mellitus and pancreatic exocrine insufficiency. Open surgery is the traditional approach to pancreatic resection. However, recent advances in laparoscopic surgery have led to laparoscopic near-total pancreatectomy for diffuse lesions and laparoscopic distal pancreatectomy for focal lesions distal to the head of the pancreas.
Introduction Persistent Hyperinsulinaemic Hypoglycaemia in infancy (PHHI or congenital hyperinsulinism, CHI) represents a group of clinically, genetically, and morphologically heterogeneous disorders characterised by dysregulation of insulin secretion from pancreatic β-cells. It is the most frequent cause of persistent hypoglycaemia in neonates and infants. It is extremely important to make a rapid diagnosis of PHHI and institute immediate appropriate management to prevent the potentially associated complications like epilepsy, cerebral palsy and neurological impairment.1 Patients with PHHI have increased risk of brain injury secondary to the metabolic actions of insulin, which acts by driving glucose into the insulin sensitive tissues (skeletal muscle and adipose tissue) and by inhibiting glucose production by glycolysis and gluconeogenesis. Unregulated insulin secretion also inhibits lipolysis and ketone body synthesis; hence the brain is deprived of both its primary and secondary energy sources (glucose & ketone bodies).2 PHHI typically presents in the newborn period with severe hypoglycaemia but can also present in the infancy and childhood periods where it tends to be milder.
The clinical presentation of PHHI can vary and patients present either with mild non-specific symptoms of hypoglycemia (such as poor feeding, lethargy and irritability) or more severe symptoms (such as apnoea, seizures or even coma). PHHI be congenital or secondary to certain risk factors like birth asphyxia, intra-uterine growth retardation3, maternal diabetes mellitus or associated with various developmental syndromes like Beckwith-Wiedemann syndrome or metabolic conditions like congenital disorders of glycosylation (CDG syndromes).4 In most forms of PHHI the hypoglycaemia typically presents during fasting but in some cases the hypoglycaemia is provoked by protein/leucine loading or even exercise. In older children and adolescents presenting with recurrent hypoglycaemia, insulinoma should be considered. Insulinomas can also be a part of multiple endocrine neoplasia syndrome
type 1 (MEN1) and hence a family history may provide a diagnostic clue in the familial cases. The clinical presentation can vary from completely asymptomatic hypoglycaemia to severe disease unresponsive to medication needing surgical intervention.5
Histologically, PHHI is classified into three subgroups: diffuse, focal, and atypical forms.6, 7. Focal disease is usually sporadic in inheritance and diffuse disease is inherited in an autosomal recessive or dominant manner. In atypical disease, the histological abnormalities may be diffuse along with presence of normal and abnormal islets. 8 Diffuse disease is a more common form of PHHI and affects the entire pancreas whilst focal disease affects only a certain area of pancreas. Recent advances in 18F-fluoro-L-dihydroxyphenylalanine (18FDOPA) PET/CT have successfully changed the surgical approach in patients with PHHI.9 The combined biochemical information and anatomical data gathered using PET scan provides a very useful tool for the surgeon in guiding limited resection of the focal lesion. 5, 10
Mutations in genes which play a role in regulating insulin secretion underlie the genetic basis of PHHI. So far, mutations in eight different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) that lead to dysregulated secretion of insulin have been described.4, 11, 12
Recessive inactivating mutations in the ABCC8 and KCNJ11 genes which encode the SUR1 (sulfonylurea receptor 1) and Kir6.2 subunits of ATP sensitive potassium channel (KATP channel) respectively, are the most common causes of medically unresponsive diffuse PHHI.12, 13 Majority of the patients with PHHI due ABCC8/KCNJ11 mutations are diazoxideunresponsive and require near-total pancreatectomy.14
After near total pancreatectomy,
patients continue to have either persistent hypoglycaemia or develop insulin-dependent diabetes mellitus, indicating the need for alternative therapeutic options for this group of patients. 14, 15 In one study on 105 patients, 59% had persistent hypoglycaemia up to 5 years
post pancreatectomy
16
. In addition, 100% of them developed diabetes mellitus in early
adolescence.16
This review article gives an overview of the clinical presentation, molecular basis, diagnosis and medical and surgical management of PHHI.
Pathophysiology of PHHI PHHI is associated with an increased risk of brain injury secondary to the metabolic actions of insulin. Inappropriate insulin secretion leads increased glucose consumption, suppression of endogenous glucose production by inhibiting glycogenolysis and gluconeogenesis and thereby causes hypoglycaemia. More importantly insulin inhibits lipolysis, free fatty acid production and ketogenesis, depriving the brain of its alternative energy substrate (ketone bodies).2, 17 Therefore it is extremely important to keep blood glucose levels in the normal range.
Abnormalities in key genes that play a role in regulating insulin secretion underlie the genetic basis of PHHI. Mutations in these genes in a recessive or dominant manner alter the normal physiological mechanisms that regulate glucose metabolism and insulin secretion. Figure 1 outlines the most common genetic cause of PHHI involving ABCC8 and KCNJ11 genes (which encode for subunits (SUR1 and KIR6.2) of the ATP sensitive K+ (KATP) channel).13, 18 Recessive inactivating mutations in ABCC8/KCNJ11 reduces or completely abolishes the activity of the KATP channel, leading to unregulated insulin secretion despite severe hypoglycaemia (see figure 1).12, 19 Dominant inactivating mutations in ABCC8 and KCNJ11 usually cause PHHI with a milder phenotype
20, 21
, although medically unresponsive forms
have been reported recently.12
Other rare forms of PHHI involve mutations in the genes that encodes enzymes responsible for insulin secretion from the pancreatic β-cells. These include dominant forms due to
mutations in the GLUD1 (encoding the enzyme glutamate dehydrogenase associated with a high serum ammonia level)22, GK (encoding the enzyme glucokinase)23 and SLC16A1 (encoding the monocarboxylate transporter MCT-1) genes.4, form
of
PHHI
12, 24
Another rare recessive
involves defects in the enzyme short-chain L-3-hydroxyacyl-CoA
dehydrogenase (SCHAD) which is encoded by the HADH gene.25 More recently, heterozygous loss-of-function mutations in the Hepatocyte Nuclear Factor 4A (HNF4A) gene resulting in transient or persistent PHHI have been described.11, 19, 26 Mutations in HNF4A not only lead to PHHI but also to maturity-onset diabetes of the young (MODY). Virtually all of the above types of PHHI are medically responsive and will not require surgery.
Clinical presentation and diagnosis Typically new-borns with PHHI have markedly reduced fasting tolerance (less than 1 hour). Patients with hypoglycaemia can present with non-specific symptoms like poor feeding, lethargy etc. If hypoglycaemia is not treated promptly then they can develop apnoea, seizures or even coma.6 A powerful clue to the dysregulated insulin secretion is the increased intravenous glucose infusion rate required to maintain normoglycaemia (>8mg/kg/min with normal being 4-6mg/kg/min). Biochemically, there is inappropriate concentration of serum insulin (and/or c-peptide) for the level of blood glucose (spontaneous or provoked).27 Children also have inappropriately low levels of serum ketone bodies and fatty acids during the hypoglycaemic episode. Fetal hyperinsulinaemia also accounts for the hypertrophic cardiomyopathy and hepatomegaly (increased storage of glucose as glycogen) that is commonly observed in patients with PHHI. It is this metabolic profile (hypoglycaemia associated with inappropriately low fatty acids and ketone bodies) which increases the risk of brain damage in PHHI patients.27
Treatment of HH It is vital to make a prompt diagnosis and institute immediate management of PHHI as delay in treatment may cause severe brain damage and permanent neurodevelopmental
disorders.1,
7, 15, 19, 27, 28-31
. Treatment of PHHI includes medical, surgical or sometimes
combination therapies (Table 1). The primary goal of therapy is to achieve normoglycaemia and restore ability of ketone bodies production as glucose and ketones provide main and alternative energy requirements for the brain. In the treatment of PHHI, clinicians should focus on corrections of two metabolic disarrangements - to achieve a safe normal blood glucose level (generally recommended as >63mg/dl or >3.5mmol/L) and to inhibit inappropriate insulin secretion.7,
14
The rise in blood glucose to a safety level can be
achieved by either administering additional glucose (via intravenous/oral high caloriecarbohydrate diet) or increase endogenous glucose production by administration of glycogenolytic and gluconeogenic hormones such as glucagon.19
On the other hand,
decrease in the serum insulin will require medications that inhibit insulin secretion from β-cell (diazoxide, octreotide, etc.) and/or removal of certain part of pancreatic β-cells through a surgical operation (pancreatectomy).
Emergency management of hypoglycaemia Intravenous glucose infusion: In those children with symptomatic hypoglycaemia (eg seizure etc) or hypoglycaemia which is unresponsive to oral feeds, immediate treatment with an intravenous bolus of 2mls/kg 10% glucose should be administered. After the intravenous bolus an intravenous glucose infusion (glucose rate of over 6-8 mg/kg/min) should be commenced to keep the blood glucose >63mg/dl (3.5mmol/l) whilst undergoing investigations and planning of long-term therapy.
Glucagon: In emergency situations like symptomatic hypoglycaemia, seizures and unable to get venous access, intramuscular glucagon administration increases blood glucose within a few minutes.15,
19, 27, 31
Glucagon induces glycogenolysis and releases hepatic glucose
stores. Glucagon also stimulates gluconeogenesis, ketogenesis and lipolysis. Although it is generally used in emergency situations, successful long-term therapy with subcutaneous infusion has been reported.28 It can be used alone and in combination with octreotide in
severe PHHI to achieve normoglycaemia during the investigations and planning of long-term treatment. Glucagon in the high doses (>20µg/kg/h) stimulates insulin secretion and can cause rebound hypoglycaemia.32 Frequent feeding: This may be difficult due to food aversion in PHHI patients and side effects of medicines administered such as diazoxide. On the other hand oral feeding may stimulate insulin secretagogues such as incretins that increase requirement of glucose infusion and causes hypoglycaemic episodes.33
Long-term medical therapy Diazoxide Diazoxide, a potent inhibitor of insulin secretion, is the cornerstone of medical treatment for PHHI. It is used as a first line drug in all types of PHHI.1, 15, 19, 27, 31, 34 Diazoxide binds to the SUR1 subunit of KATP channel, which opens up and activates intact KATP channels, thereby reducing the insulin secretion. For this it requires an intact KATP channel. Hence, children with diffuse disease due to inactivating mutations in ABCC8 and KCNJ11 and most patients with focal lesions are unresponsive to diazoxide.15,
17, 19, 27, 35, 36
Diazoxide is usually well
tolerated and availability of oral formulation increases its compliance.
The most common acute side effect is fluid retention. The fluid retention is mostly observed in the neonatal period, and may cause congestive heart failure.37 A thiazide diuretic, Chlorothiazide is usually used in combination to prevent fluid retention and for synergistic effect on the suppression of insulin secretion.15,
17, 27, 31
Therefore, routine use of thiazide
diuretics is not necessary in older children if there is no clinical evidence of fluid retention. Other frequent side effects are nausea, vomiting, loss of appetite and hypertrichosis. It has been shown that diazoxide may cause paradoxical hypoglycaemia when used in higher doses (20 mg/kg/day).38 Table 2 provides detailed information of diazoxide.37, 39
Nifedipine Nifedipine is a calcium-channel blocker and it inhibits insulin secretion by inactivation of voltage gated calcium-channels. Several patients with Nifedipine responsive forms of PHHI have been reported. 40-46 Octreotide Octreotide is a long-acting analogue of the natural hormone, somatostatin, which has potent inhibitory effects on the release of insulin from pancreatic β-cells. Octreotide shows a high degree of affinity for somatostatin receptors (SSTR) 2 and 3 and little or no binding to SSTR 1. Somatostatin and its analogs can inhibit insulin secretion by activation of SSTR 5, which is mediated by stimulation of the Gi/Go protein. In pancreatic β-cells, activation of SSTR 5 inhibits calcium mobilization and acetylcholine activity, and decreases insulin gene promoter activity, resulting in reduced insulin biosynthesis. Somatostatin also exhibits an effect on insulin secretion distal from the inhibition of Ca2+ mobilization and adenylate cyclase inhibition.
Although octreotide has an effect of rapid and sharp increase on the blood glucose at the administration of first doses, a tolerance to its effects may be observed at the subsequent 23 doses (tachyphylaxis) which is generally transient and can be managed by dose adjustment.15, 19, 27 A detailed description of dose, route of administration and side effects of octreotide as shown in Table 2. Recently, a long-acting somatostatin analogue, Lanreotide has been used in the treatment of PHHI patients as a four weekly deep intramuscular injections.47-49 Clinical experience with this formulation is currently limited, however it is expected to be an alternative medicine for those children on multiple daily octreotide injection.
In some patient’s frequent high volume, calorie and glucose-enriched oral feedings and continuous enteral feeding contribute to the success of medical therapy. An important issue
in these patient’s is disease and drug induced food aversion and vomiting.50 In some patients a gastrostomy and anti-reflux surgery is might be required to allow the delivery of frequent bolus and continuous overnight feeds. Long-term successful management with long-term subcutaneous octreotide and glucagon injections/infusion in combination with frequent feedings has been reported. 28, 51-53
New medicines and future therapies LAR-octreotide/Lanreotide: Lanreotide, a synthetic octapeptide somatostatin analogue, has been widely used in adults for the treatment of growth hormone excess due to pituitary adenoma. Recently, two prolonged released formulation LAR-octreotide and Lanreotide have been used (IM injection) in a few numbers of patients with PHHI successfully.47, 48, 49 Although the number of patients studied so fat is limited, all patients had same or better response to long acting octreotide than previous therapies like three to four times daily short acting octreotide injections and intensive feeding regime. Even in the youngest patient who was only seven months old when Lanreotide was commenced, except for mild local reaction such as hematoma, none of severe side effects was observed. Administration of four weekly injections not only increases compliance but also improves quality of life for patients and their families.47,
48, 49
However more studies are required to look into the long-term
effectiveness of this medication.
GLP1 receptor antagonist Exendin-(9-39): It has been reported that a GLP-1 receptor antagonist, Exendin-(9-39) elevates fasting glucose in adult human subjects with KATP PHHI.54 It has been suggested GLP-1 receptor antagonist represents a novel therapeutic target to control hypoglycaemia in PHHI patients. However, this drug needs further clinical experiences on its effectively, safety and pharmacokinetics to be a therapeutic option in children with PHHI.
Surgical therapy Differentiation of the histologic subtypes of HH The differentiation between the two the histological subtype’s (diffuse and focal) is important from the surgical management point of view.1, 7, 14, 15, 17, 19, 27 While the diffuse form of PHHI affects all the β-cells within the islets of Langerhans (Figure 2) the focal form is characterised by a group of affected β-cells surrounded by normal tissue (Figure 2). Presence of β-cells with enlarged nuclei and normal cells around the lesion are the histological hallmark for the diagnosis of focal disease.27,
31
Focal pancreatic lesions are
generally 2-10mm in size and appear as small regions of islet adenomatosis (nodular hyperplasia of islet-like cell clusters, including ductuloinsular complexes).
Surgical procedures for the focal and diffuse forms of PHHI are quite different. Focal disease can be cured with a limited lesionectomy this reducing the risk of diabetes mellitus and exocrine pancreatic deficiency. But diffuse disease requires a near total (95-98%) pancreatectomy with a high risk of developing postsurgical diabetes mellitus and exocrine pancreatic insufficiency that will need lifelong insulin and pancreatic enzyme replacement therapy.1, 15, 16, 17, 27, 31, 55
Since the clinical presentation and biochemical features of focal and diffuse disease are indistinguishable, the pre-operative differentiation of both subtypes is critically important. Conventional radiological imaging methods such as Magnetic Resonance Imaging (MRI) and Computerized Tomography (CT) scans fail to localize the focal lesions. Genetic analysis for mutations in ABCC8/KCNJ11, with combination of recently described 18F-DOPA-PET/CT scanning allows differentiating focal and diffuse disease with a high sensitivity and specificity. 9, 19, 27, 56-64
The focal form of PHHI has been reported in about 40–65% of all patients treated surgically and is associated with a paternally inherited mutation in ABCC8/KCNJ11 genes (located in the 11p15.1 region) and loss of the maternal 11p15 allele, in the β-cells of focal adenomatous lesion.21,
27, 35, 65
The loss of the maternal allele results in hemizygosity or
homozygosity of the inherited mutation in this area (paternal uniparental disomy, UPD). Homozygous or compound heterozygous mutations in the ABCC8 (SUR1) and KCNJ11 (Kir6.2) causes diffuse disease which involves all β-cells in the pancreas.
Although genetic mutation analysis might aid in predicting focal and diffuse disease, positron emission tomography scan performed with the Fluorine 18 L-3, 4-dihydroxyphenyalanine (18F-DOPA-PET) is required for the precise pre-operative localisation of the focal lesion within the pancreas.19, 27, 56-64 Thus, imaging with 18F-DOPA-PET should be performed in all patients who are thought to have a focal lesion. Rarely patients have been described with atypical histological forms either atypical focal, atypical diffuse or ectopic β-cells hyperplasia which do not show classical features of focal or diffuse disease.27, 66
The principle of 18F-DOPA-PET analysis is based on the ability of L-DOPA uptake by β-cells and its conversion into dopamine by DOPA decarboxylase enzyme which is expressed in the pancreatic β-cells. 18F-DOPA is a DOPA analogue and enters into β-cells, and then stored in the vesicles. Its uptake and conversion to dopamine by DOPA decarboxylase in the βcells can be traced by the positron-emitting compound. The uptake of the positron emitting tracer 18F-DOPA-PET is increased in β-cells with a high rate of insulin synthesis and secretion compared to unaffected areas allowing visualization of the focal lesion.
Demonstration of increased activity of DOPA decarboxylase by 18F-DOPA-PET in combination with an enhanced CT imaging can successfully differentiate diffuse and focal βcell hyperplasia. Sensitivity and specificity of 18F-DOPA-PET/CT to differentiate focal and diffuse PHHI and localization of focal lesion have been reported between 88% and 94% with
an accuracy of 100%. Therefore, this technique has radically changed the surgical approach to patients with medically unresponsive PHHI.
Surgical Management of HH A multidisciplinary approach to patients with the focal form of PHHI is very important to distinguish from diffuse disease, localize focal lesions, and perform partial pancreatectomy with cure in most patients.67 While the focal form of PHHI requires a limited lesionectomy, diffuse disease may require a near-total pancreatectomy.5, 66, 68, 69 Complete excision of the focal lesion will require intraoperative biopsies to look for abnormal cells at the margin. Additional resections until margins are clear may need to be performed to avoid redoing of surgery.
Completely excision of focal lesion may provide a cure from hypoglycaemia without developing post-operative complications like diabetes mellitus and exocrine pancreas insufficiency. Laje P et. al.70 showed that for large focal lesions in the pancreatic head that is not amenable to local resection alone, pancreatic head resection with Roux-en-Y pancreatico-jejunostomy is a safe and effective procedure. However, Obatake M et. al. 71 reported a patient with focal lesion in the head of the pancreas underwent pancreatic head resection preserving the main pancreatic duct to avoid pancreaticojejunostomy.
Medically unresponsive diffuse PHHI requires a near-total pancreatectomy (95-98% of the pancreas) leaving just the small triangle of pancreatic tissue between the duodenum and the common bile duct. However, up to 50% patients continue to have hypoglycaemia or they develop post-operative diabetes mellitus and exocrine pancreas insufficiency.16, 72
Laparoscopic pancreatectomy represents a new approach to the management of infants with PHHI.67, 73-77 Thus, in diffuse disease a partial pancreatectomy to get the disease milder and manage with postsurgical medical therapy can be an option. This will decrease
postoperative risk of diabetes mellitus and exocrine pancreas insufficiency that need lifelong insulin and pancreatic enzyme replacement therapy. Furthermore, the low risk of intraabdominal adhesions during laparoscopic surgery can give the opportunity of re-operation without surgical complications.
Summary PHHI is one of the most common causes of persistent hypoglycaemia in children. Prompt diagnosis and management of these children is extremely vital to avoid neurological handicap. It is vital for pre-operative histological differentiation of PHHI as the surgical treatment of the two major subgroups i.e diffuse and focal is radically different. Genetic analysis and 18F-DOPA-PET/CT scan allows differentiation between diffuse and focal disease. 18F-DOPA-PET/CT helps in determining the size and location of focal lesions and removal of the focal lesion can cure the patient. For focal lesions in the body or tail of the pancreas, laparoscopic distal pancreatectomy is usually performed. However, partial excision of the head of the pancreas and pancreatico-jejunostomy is required for more proximal focal lesions. The management of the severe diffuse form of the disease still remains a challenge as the treatment options are unsatisfactory with lifelong implications. Near total pancreatectomy is necessary in those children unresponsive to medical therapy, but carries a risk of developing postoperative endocrine and exocrine insufficiency. Laparoscopic near-total pancreatectomy is an option in centres with advanced laparoscopic expertise.
Disclosure Summary: The authors have nothing to disclose
Legends Figure 1: β-cell with recessive inactivating mutations in ABCC8 or KCNJ11 cause continuous membrane depolarization and subsequent calcium influx, which result in unregulated insulin secretion. Figure 2: Histological subtypes of CHI The focal form is localised to a single region of the pancreas whereas diffuse disease affects the whole pancreas. The histology shows marked hyperplasia of the islets in focal disease. Figure 3: Near-total pancreatectomy. The shaded area indicates the remaining pancreas after resection, leaving pancreatic tissue around the common bile duct and along the medial border of the duodenum Figure 4: Focal CHI. Focal PHHI A: Lesion in the body or tail of pancreas (brown circular area) and B: Lesion in the head or neck of pancreas (orange circular area). Surgery for A: Laparoscopic distal pancreatectomy. Surgery for B: Open excision of focal lesion and pancreaticojejunostomy. Figure 5: 18F-DOPA-PET/CT scan of focal lesion located in the head of pancreas Table 1: Summary of treatment and follow up of PHHI patients
Table 2: Summary of the medications used their mechanisms of action and side effects. Diazoxide is the mainstay of therapy for patients with PHHI. However the vast majority patients with defects in the KATP channels will not respond to diazoxide.
Figure 1: Recessive inactivating mutations in ABCC8 or KCNJ11 cause continuous β-cell membrane depolarization and subsequent calcium influx, which result in unregulated insulin secretion.
Mutations in KATP channel
Glucose
SUR1 Kir6.2
Glycolysis
TCA cycle
ATP closes KATP channel
K+
Membrane
ADP ATP
depolarisation
Secretary vesicles Ca2+ causes exocytosis
Insulin
Calcium influx
Figure 2: Histologic subtypes (focal and diffuse) of PHHI (Figure adapted from Hussain et. al. congenital hyperinsulinism. Endocrine surgery in Children)
Figure 3: Near-total pancreatectomy. The shaded area indicates the remaining pancreas after resection, leaving behind pancreatic tissue around the common bile duct and along the medial border of the duodenum66, 68, 69
Figure 4: Focal CHI. A, Lesion in the body or tail of pancreas (brown circular area) and B, Lesion in the head or neck of pancreas (orange circular area).66, 68-71 Surgery for A: Laparoscopic distal pancreatectomy. Surgery for B: Open excision of focal lesion and pancreaticojejunostomy.
A B
Figure 5 : The Standard Uptake Value (SUV) of Fluorine-18-L-3,4-dihydroxyphenylalanine is highest in the head of the pancreas (5.0) compared to the body and tail of the pancreas. At surgery a focal lesion was found located between the superior mesenteric vein and portal vein. (Figure adapted from Hussain et. al. congenital hyperinsulinism. Endocrine surgery in Children)
Table 1. Summary of treatment strategies and follow up for PHHI patients 1. Emergency treatment a. Intravenous glucose infusion (insertion of central venous catheter may be required) b. Glucagon injection c. Frequent feeding 2. Long-term medical treatment i) Diazoxide ii) Chlorothiazide iii) Nifedipine iv) Octreotide and glucagon infusion v) New medicines (long acting octreotide, lanreotide etc.) 3. Arrangement of feeding i. Individualized feeding plan according to fasting tolerance ii. Assessment of protein sensitivity and arrangement of food content iii. Bolus feeding with high calorie and carbohydrate solutions (eg maxijule etc) iv. Overnight continuous intra-gastric feeding v. Corn-starch vi. Anti-reflux medications and solid/semisolid feeds instead of liquids if appropriate 4. Surgical management i. Maintenance of normoglycaemia ii. Differentiation of histologic subtype iii. Lesionectomy for focal disease (laparoscopic or open) iv. Pancreatectomy for diffuse disease a. Partial pancreatectomy in combination with medical therapy b. Subtotal pancreatectomy (removal of up to 95% of pancreas) c. Near-total pancreatectomy (removal of 95 to 98% of pancreas) v. Assessment of postsurgical complications and their management a. Insulin therapy for diabetes mellitus b. Replacement by pancreatic enzymes for exocrine pancreatic insufficiency 5. Other surgical interventions (if required) i. Surgery for gastro-oesophageal reflux ii. PEG gastrostomy 6. Follow up i. Growth ii. Neurological outcome iii. Monitor for side effects of the medications iv. Assessment periodically for fasting tolerance and dose adjustment v. Assessment for postsurgical complications (diabetes and exocrine pancreas insufficiency)
Table 2: Drugs for medical therapy of PHHI
Diazoxide
Route of administrati on
Dose
Oral
5-20 mg/kg/day, in 3 divided doses
Mode of action
Side effects
Bind to SUR1 subunit of KATP channels, opens the channels and inhibits insulin secretion
Common: Water and salt retention, hypertrichosis, loss of appetite
Needs an intact KATP channel activity to work properly
Rare: Cardiac failure, hyperuricaemia, blood dyscrasias (bone marrow suppression, anaemia, eosinophilia etc.), paradoxical hypoglycemia
Chlorothiazid e
Oral
7-10 mg/kg/day, in Prevents fluid 2 divided doses retention, synergistic effects with diazoxide on KATP channels to inhibit insulin secretion
Nifedipine
Oral
0.25-25 mg/kg/day, Inhibits Ca-channels in 2-3 divided of the beta-cell doses membrane
Octreotide
s.c
5-35 µg/kg/day, divided to 3-4 doses or continuous subcutaneous infusion
Activation of SSTR 5 inhibits calcium mobilization and acetylcholine activity, and decreases insulin gene promoter activity, reduces insulin biosynthesis and insulin secretion.
Hyponatraemia, hypokalaemia
Hypotension
Acute: Anorexia, nausea, abdominal discomfort, diarrhoea, drug induced hepatitis, long QT syndrome, tachyphylaxis, necrotizing enterocolitis Long-term: Decreases intestinal motility, bile sludge and gallstone, suppression of pituitary hormones
(Growth hormone, TSH) Glucagon
s.c/i.m bolus or sc/iv infusion
0.02 mg/kg/dose or G-protein coupled 5-10 µg/kg/hour activation of infusion adenylate cylase, increases cAMP, Induces glycogenolysis and gluconeogenesis
Nausea, vomiting, skin rash and rebound hypoglycemia in high doses (>20 µ/kg/hour) due to paradoxical activation of insulin secretion
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Persistent Hyperinsulinaemic Hypoglycaemia in infancy Pratik Shah, Huseyin Demirbilek, Khalid Hussain
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PII: DOI: Reference:
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To appear in:
Seminars in Pediatric Surgery
Cite this article as: Pratik Shah, Huseyin Demirbilek, Khalid Hussain, Persistent Hyperinsulinaemic Hypoglycaemia in infancy, Seminars in Pediatric Surgery, http: //dx.doi.org/10.1053/j.sempedsurg.2014.03.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Persistent Hyperinsulinaemic Hypoglycaemia in infancy Pratik Shah1, Huseyin Demirbilek 1, Khalid Hussain1 1
Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit,
Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH & Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London WC1N 3JH Corresponding author Dr. K. Hussain Developmental Endocrinology Research Group Clinical and Molecular Genetics Unit Institute of Child Health University College London, 30 Guilford Street, London WC1N 1EH Tel: ++44 (0)20 7 905 2128 Fax: ++44 (0)20 7 404 6191 Email: [email protected]
Key Words: Hyperinsulinaemic hypoglycaemia, diffuse, focal, Word Count: Abstract: 220 Manuscript: 3600
Abstract Context: Persistent Hyperinsulinaemic Hypoglycaemia in Infancy (PHHI) is a heterogeneous condition characterised by unregulated insulin secretion in response to a low blood glucose level. It is the most common cause of severe and persistent hypoglycaemia in neonates. It is extremely important to recognise this condition early and institute appropriate management to prevent significant brain injury leading to complications like epilepsy, cerebral palsy and neurological impairment. Histologically, PHHI is divided mainly into three types - diffuse, focal and atypical disease. 18F-DOPA-PET/CT (Fluorine-18-L-3,4-dihydroxyphenylalanine positron emission tomography) scan allows differentiation between diffuse and focal disease. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localised to a small region of the pancreas. The molecular basis of PHHI involves defects in key genes (ABCC8, KCNJ11, GCK, SLC16A1, HADH, UCP2, HNF4A and GLUD1) which regulate insulin secretion. Focal lesions are cured by lesionectomy whereas diffuse disease (unresponsive to medical therapy) will require a near total pancreatectomy with a risk of developing diabetes mellitus and pancreatic exocrine insufficiency. Open surgery is the traditional approach to pancreatic resection. However, recent advances in laparoscopic surgery have led to laparoscopic near-total pancreatectomy for diffuse lesions and laparoscopic distal pancreatectomy for focal lesions distal to the head of the pancreas.
Introduction Persistent Hyperinsulinaemic Hypoglycaemia in infancy (PHHI or congenital hyperinsulinism, CHI) represents a group of clinically, genetically, and morphologically heterogeneous disorders characterised by dysregulation of insulin secretion from pancreatic β-cells. It is the most frequent cause of persistent hypoglycaemia in neonates and infants. It is extremely important to make a rapid diagnosis of PHHI and institute immediate appropriate management to prevent the potentially associated complications like epilepsy, cerebral palsy and neurological impairment.1 Patients with PHHI have increased risk of brain injury secondary to the metabolic actions of insulin, which acts by driving glucose into the insulin sensitive tissues (skeletal muscle and adipose tissue) and by inhibiting glucose production by glycolysis and gluconeogenesis. Unregulated insulin secretion also inhibits lipolysis and ketone body synthesis; hence the brain is deprived of both its primary and secondary energy sources (glucose & ketone bodies).2 PHHI typically presents in the newborn period with severe hypoglycaemia but can also present in the infancy and childhood periods where it tends to be milder.
The clinical presentation of PHHI can vary and patients present either with mild non-specific symptoms of hypoglycemia (such as poor feeding, lethargy and irritability) or more severe symptoms (such as apnoea, seizures or even coma). PHHI be congenital or secondary to certain risk factors like birth asphyxia, intra-uterine growth retardation3, maternal diabetes mellitus or associated with various developmental syndromes like Beckwith-Wiedemann syndrome or metabolic conditions like congenital disorders of glycosylation (CDG syndromes).4 In most forms of PHHI the hypoglycaemia typically presents during fasting but in some cases the hypoglycaemia is provoked by protein/leucine loading or even exercise. In older children and adolescents presenting with recurrent hypoglycaemia, insulinoma should be considered. Insulinomas can also be a part of multiple endocrine neoplasia syndrome
type 1 (MEN1) and hence a family history may provide a diagnostic clue in the familial cases. The clinical presentation can vary from completely asymptomatic hypoglycaemia to severe disease unresponsive to medication needing surgical intervention.5
Histologically, PHHI is classified into three subgroups: diffuse, focal, and atypical forms.6, 7. Focal disease is usually sporadic in inheritance and diffuse disease is inherited in an autosomal recessive or dominant manner. In atypical disease, the histological abnormalities may be diffuse along with presence of normal and abnormal islets. 8 Diffuse disease is a more common form of PHHI and affects the entire pancreas whilst focal disease affects only a certain area of pancreas. Recent advances in 18F-fluoro-L-dihydroxyphenylalanine (18FDOPA) PET/CT have successfully changed the surgical approach in patients with PHHI.9 The combined biochemical information and anatomical data gathered using PET scan provides a very useful tool for the surgeon in guiding limited resection of the focal lesion. 5, 10
Mutations in genes which play a role in regulating insulin secretion underlie the genetic basis of PHHI. So far, mutations in eight different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) that lead to dysregulated secretion of insulin have been described.4, 11, 12
Recessive inactivating mutations in the ABCC8 and KCNJ11 genes which encode the SUR1 (sulfonylurea receptor 1) and Kir6.2 subunits of ATP sensitive potassium channel (KATP channel) respectively, are the most common causes of medically unresponsive diffuse PHHI.12, 13 Majority of the patients with PHHI due ABCC8/KCNJ11 mutations are diazoxideunresponsive and require near-total pancreatectomy.14
After near total pancreatectomy,
patients continue to have either persistent hypoglycaemia or develop insulin-dependent diabetes mellitus, indicating the need for alternative therapeutic options for this group of patients. 14, 15 In one study on 105 patients, 59% had persistent hypoglycaemia up to 5 years
post pancreatectomy
16
. In addition, 100% of them developed diabetes mellitus in early
adolescence.16
This review article gives an overview of the clinical presentation, molecular basis, diagnosis and medical and surgical management of PHHI.
Pathophysiology of PHHI PHHI is associated with an increased risk of brain injury secondary to the metabolic actions of insulin. Inappropriate insulin secretion leads increased glucose consumption, suppression of endogenous glucose production by inhibiting glycogenolysis and gluconeogenesis and thereby causes hypoglycaemia. More importantly insulin inhibits lipolysis, free fatty acid production and ketogenesis, depriving the brain of its alternative energy substrate (ketone bodies).2, 17 Therefore it is extremely important to keep blood glucose levels in the normal range.
Abnormalities in key genes that play a role in regulating insulin secretion underlie the genetic basis of PHHI. Mutations in these genes in a recessive or dominant manner alter the normal physiological mechanisms that regulate glucose metabolism and insulin secretion. Figure 1 outlines the most common genetic cause of PHHI involving ABCC8 and KCNJ11 genes (which encode for subunits (SUR1 and KIR6.2) of the ATP sensitive K+ (KATP) channel).13, 18 Recessive inactivating mutations in ABCC8/KCNJ11 reduces or completely abolishes the activity of the KATP channel, leading to unregulated insulin secretion despite severe hypoglycaemia (see figure 1).12, 19 Dominant inactivating mutations in ABCC8 and KCNJ11 usually cause PHHI with a milder phenotype
20, 21
, although medically unresponsive forms
have been reported recently.12
Other rare forms of PHHI involve mutations in the genes that encodes enzymes responsible for insulin secretion from the pancreatic β-cells. These include dominant forms due to
mutations in the GLUD1 (encoding the enzyme glutamate dehydrogenase associated with a high serum ammonia level)22, GK (encoding the enzyme glucokinase)23 and SLC16A1 (encoding the monocarboxylate transporter MCT-1) genes.4, form
of
PHHI
12, 24
Another rare recessive
involves defects in the enzyme short-chain L-3-hydroxyacyl-CoA
dehydrogenase (SCHAD) which is encoded by the HADH gene.25 More recently, heterozygous loss-of-function mutations in the Hepatocyte Nuclear Factor 4A (HNF4A) gene resulting in transient or persistent PHHI have been described.11, 19, 26 Mutations in HNF4A not only lead to PHHI but also to maturity-onset diabetes of the young (MODY). Virtually all of the above types of PHHI are medically responsive and will not require surgery.
Clinical presentation and diagnosis Typically new-borns with PHHI have markedly reduced fasting tolerance (less than 1 hour). Patients with hypoglycaemia can present with non-specific symptoms like poor feeding, lethargy etc. If hypoglycaemia is not treated promptly then they can develop apnoea, seizures or even coma.6 A powerful clue to the dysregulated insulin secretion is the increased intravenous glucose infusion rate required to maintain normoglycaemia (>8mg/kg/min with normal being 4-6mg/kg/min). Biochemically, there is inappropriate concentration of serum insulin (and/or c-peptide) for the level of blood glucose (spontaneous or provoked).27 Children also have inappropriately low levels of serum ketone bodies and fatty acids during the hypoglycaemic episode. Fetal hyperinsulinaemia also accounts for the hypertrophic cardiomyopathy and hepatomegaly (increased storage of glucose as glycogen) that is commonly observed in patients with PHHI. It is this metabolic profile (hypoglycaemia associated with inappropriately low fatty acids and ketone bodies) which increases the risk of brain damage in PHHI patients.27
Treatment of HH It is vital to make a prompt diagnosis and institute immediate management of PHHI as delay in treatment may cause severe brain damage and permanent neurodevelopmental
disorders.1,
7, 15, 19, 27, 28-31
. Treatment of PHHI includes medical, surgical or sometimes
combination therapies (Table 1). The primary goal of therapy is to achieve normoglycaemia and restore ability of ketone bodies production as glucose and ketones provide main and alternative energy requirements for the brain. In the treatment of PHHI, clinicians should focus on corrections of two metabolic disarrangements - to achieve a safe normal blood glucose level (generally recommended as >63mg/dl or >3.5mmol/L) and to inhibit inappropriate insulin secretion.7,
14
The rise in blood glucose to a safety level can be
achieved by either administering additional glucose (via intravenous/oral high caloriecarbohydrate diet) or increase endogenous glucose production by administration of glycogenolytic and gluconeogenic hormones such as glucagon.19
On the other hand,
decrease in the serum insulin will require medications that inhibit insulin secretion from β-cell (diazoxide, octreotide, etc.) and/or removal of certain part of pancreatic β-cells through a surgical operation (pancreatectomy).
Emergency management of hypoglycaemia Intravenous glucose infusion: In those children with symptomatic hypoglycaemia (eg seizure etc) or hypoglycaemia which is unresponsive to oral feeds, immediate treatment with an intravenous bolus of 2mls/kg 10% glucose should be administered. After the intravenous bolus an intravenous glucose infusion (glucose rate of over 6-8 mg/kg/min) should be commenced to keep the blood glucose >63mg/dl (3.5mmol/l) whilst undergoing investigations and planning of long-term therapy.
Glucagon: In emergency situations like symptomatic hypoglycaemia, seizures and unable to get venous access, intramuscular glucagon administration increases blood glucose within a few minutes.15,
19, 27, 31
Glucagon induces glycogenolysis and releases hepatic glucose
stores. Glucagon also stimulates gluconeogenesis, ketogenesis and lipolysis. Although it is generally used in emergency situations, successful long-term therapy with subcutaneous infusion has been reported.28 It can be used alone and in combination with octreotide in
severe PHHI to achieve normoglycaemia during the investigations and planning of long-term treatment. Glucagon in the high doses (>20µg/kg/h) stimulates insulin secretion and can cause rebound hypoglycaemia.32 Frequent feeding: This may be difficult due to food aversion in PHHI patients and side effects of medicines administered such as diazoxide. On the other hand oral feeding may stimulate insulin secretagogues such as incretins that increase requirement of glucose infusion and causes hypoglycaemic episodes.33
Long-term medical therapy Diazoxide Diazoxide, a potent inhibitor of insulin secretion, is the cornerstone of medical treatment for PHHI. It is used as a first line drug in all types of PHHI.1, 15, 19, 27, 31, 34 Diazoxide binds to the SUR1 subunit of KATP channel, which opens up and activates intact KATP channels, thereby reducing the insulin secretion. For this it requires an intact KATP channel. Hence, children with diffuse disease due to inactivating mutations in ABCC8 and KCNJ11 and most patients with focal lesions are unresponsive to diazoxide.15,
17, 19, 27, 35, 36
Diazoxide is usually well
tolerated and availability of oral formulation increases its compliance.
The most common acute side effect is fluid retention. The fluid retention is mostly observed in the neonatal period, and may cause congestive heart failure.37 A thiazide diuretic, Chlorothiazide is usually used in combination to prevent fluid retention and for synergistic effect on the suppression of insulin secretion.15,
17, 27, 31
Therefore, routine use of thiazide
diuretics is not necessary in older children if there is no clinical evidence of fluid retention. Other frequent side effects are nausea, vomiting, loss of appetite and hypertrichosis. It has been shown that diazoxide may cause paradoxical hypoglycaemia when used in higher doses (20 mg/kg/day).38 Table 2 provides detailed information of diazoxide.37, 39
Nifedipine Nifedipine is a calcium-channel blocker and it inhibits insulin secretion by inactivation of voltage gated calcium-channels. Several patients with Nifedipine responsive forms of PHHI have been reported. 40-46 Octreotide Octreotide is a long-acting analogue of the natural hormone, somatostatin, which has potent inhibitory effects on the release of insulin from pancreatic β-cells. Octreotide shows a high degree of affinity for somatostatin receptors (SSTR) 2 and 3 and little or no binding to SSTR 1. Somatostatin and its analogs can inhibit insulin secretion by activation of SSTR 5, which is mediated by stimulation of the Gi/Go protein. In pancreatic β-cells, activation of SSTR 5 inhibits calcium mobilization and acetylcholine activity, and decreases insulin gene promoter activity, resulting in reduced insulin biosynthesis. Somatostatin also exhibits an effect on insulin secretion distal from the inhibition of Ca2+ mobilization and adenylate cyclase inhibition.
Although octreotide has an effect of rapid and sharp increase on the blood glucose at the administration of first doses, a tolerance to its effects may be observed at the subsequent 23 doses (tachyphylaxis) which is generally transient and can be managed by dose adjustment.15, 19, 27 A detailed description of dose, route of administration and side effects of octreotide as shown in Table 2. Recently, a long-acting somatostatin analogue, Lanreotide has been used in the treatment of PHHI patients as a four weekly deep intramuscular injections.47-49 Clinical experience with this formulation is currently limited, however it is expected to be an alternative medicine for those children on multiple daily octreotide injection.
In some patient’s frequent high volume, calorie and glucose-enriched oral feedings and continuous enteral feeding contribute to the success of medical therapy. An important issue
in these patient’s is disease and drug induced food aversion and vomiting.50 In some patients a gastrostomy and anti-reflux surgery is might be required to allow the delivery of frequent bolus and continuous overnight feeds. Long-term successful management with long-term subcutaneous octreotide and glucagon injections/infusion in combination with frequent feedings has been reported. 28, 51-53
New medicines and future therapies LAR-octreotide/Lanreotide: Lanreotide, a synthetic octapeptide somatostatin analogue, has been widely used in adults for the treatment of growth hormone excess due to pituitary adenoma. Recently, two prolonged released formulation LAR-octreotide and Lanreotide have been used (IM injection) in a few numbers of patients with PHHI successfully.47, 48, 49 Although the number of patients studied so fat is limited, all patients had same or better response to long acting octreotide than previous therapies like three to four times daily short acting octreotide injections and intensive feeding regime. Even in the youngest patient who was only seven months old when Lanreotide was commenced, except for mild local reaction such as hematoma, none of severe side effects was observed. Administration of four weekly injections not only increases compliance but also improves quality of life for patients and their families.47,
48, 49
However more studies are required to look into the long-term
effectiveness of this medication.
GLP1 receptor antagonist Exendin-(9-39): It has been reported that a GLP-1 receptor antagonist, Exendin-(9-39) elevates fasting glucose in adult human subjects with KATP PHHI.54 It has been suggested GLP-1 receptor antagonist represents a novel therapeutic target to control hypoglycaemia in PHHI patients. However, this drug needs further clinical experiences on its effectively, safety and pharmacokinetics to be a therapeutic option in children with PHHI.
Surgical therapy Differentiation of the histologic subtypes of HH The differentiation between the two the histological subtype’s (diffuse and focal) is important from the surgical management point of view.1, 7, 14, 15, 17, 19, 27 While the diffuse form of PHHI affects all the β-cells within the islets of Langerhans (Figure 2) the focal form is characterised by a group of affected β-cells surrounded by normal tissue (Figure 2). Presence of β-cells with enlarged nuclei and normal cells around the lesion are the histological hallmark for the diagnosis of focal disease.27,
31
Focal pancreatic lesions are
generally 2-10mm in size and appear as small regions of islet adenomatosis (nodular hyperplasia of islet-like cell clusters, including ductuloinsular complexes).
Surgical procedures for the focal and diffuse forms of PHHI are quite different. Focal disease can be cured with a limited lesionectomy this reducing the risk of diabetes mellitus and exocrine pancreatic deficiency. But diffuse disease requires a near total (95-98%) pancreatectomy with a high risk of developing postsurgical diabetes mellitus and exocrine pancreatic insufficiency that will need lifelong insulin and pancreatic enzyme replacement therapy.1, 15, 16, 17, 27, 31, 55
Since the clinical presentation and biochemical features of focal and diffuse disease are indistinguishable, the pre-operative differentiation of both subtypes is critically important. Conventional radiological imaging methods such as Magnetic Resonance Imaging (MRI) and Computerized Tomography (CT) scans fail to localize the focal lesions. Genetic analysis for mutations in ABCC8/KCNJ11, with combination of recently described 18F-DOPA-PET/CT scanning allows differentiating focal and diffuse disease with a high sensitivity and specificity. 9, 19, 27, 56-64
The focal form of PHHI has been reported in about 40–65% of all patients treated surgically and is associated with a paternally inherited mutation in ABCC8/KCNJ11 genes (located in the 11p15.1 region) and loss of the maternal 11p15 allele, in the β-cells of focal adenomatous lesion.21,
27, 35, 65
The loss of the maternal allele results in hemizygosity or
homozygosity of the inherited mutation in this area (paternal uniparental disomy, UPD). Homozygous or compound heterozygous mutations in the ABCC8 (SUR1) and KCNJ11 (Kir6.2) causes diffuse disease which involves all β-cells in the pancreas.
Although genetic mutation analysis might aid in predicting focal and diffuse disease, positron emission tomography scan performed with the Fluorine 18 L-3, 4-dihydroxyphenyalanine (18F-DOPA-PET) is required for the precise pre-operative localisation of the focal lesion within the pancreas.19, 27, 56-64 Thus, imaging with 18F-DOPA-PET should be performed in all patients who are thought to have a focal lesion. Rarely patients have been described with atypical histological forms either atypical focal, atypical diffuse or ectopic β-cells hyperplasia which do not show classical features of focal or diffuse disease.27, 66
The principle of 18F-DOPA-PET analysis is based on the ability of L-DOPA uptake by β-cells and its conversion into dopamine by DOPA decarboxylase enzyme which is expressed in the pancreatic β-cells. 18F-DOPA is a DOPA analogue and enters into β-cells, and then stored in the vesicles. Its uptake and conversion to dopamine by DOPA decarboxylase in the βcells can be traced by the positron-emitting compound. The uptake of the positron emitting tracer 18F-DOPA-PET is increased in β-cells with a high rate of insulin synthesis and secretion compared to unaffected areas allowing visualization of the focal lesion.
Demonstration of increased activity of DOPA decarboxylase by 18F-DOPA-PET in combination with an enhanced CT imaging can successfully differentiate diffuse and focal βcell hyperplasia. Sensitivity and specificity of 18F-DOPA-PET/CT to differentiate focal and diffuse PHHI and localization of focal lesion have been reported between 88% and 94% with
an accuracy of 100%. Therefore, this technique has radically changed the surgical approach to patients with medically unresponsive PHHI.
Surgical Management of HH A multidisciplinary approach to patients with the focal form of PHHI is very important to distinguish from diffuse disease, localize focal lesions, and perform partial pancreatectomy with cure in most patients.67 While the focal form of PHHI requires a limited lesionectomy, diffuse disease may require a near-total pancreatectomy.5, 66, 68, 69 Complete excision of the focal lesion will require intraoperative biopsies to look for abnormal cells at the margin. Additional resections until margins are clear may need to be performed to avoid redoing of surgery.
Completely excision of focal lesion may provide a cure from hypoglycaemia without developing post-operative complications like diabetes mellitus and exocrine pancreas insufficiency. Laje P et. al.70 showed that for large focal lesions in the pancreatic head that is not amenable to local resection alone, pancreatic head resection with Roux-en-Y pancreatico-jejunostomy is a safe and effective procedure. However, Obatake M et. al. 71 reported a patient with focal lesion in the head of the pancreas underwent pancreatic head resection preserving the main pancreatic duct to avoid pancreaticojejunostomy.
Medically unresponsive diffuse PHHI requires a near-total pancreatectomy (95-98% of the pancreas) leaving just the small triangle of pancreatic tissue between the duodenum and the common bile duct. However, up to 50% patients continue to have hypoglycaemia or they develop post-operative diabetes mellitus and exocrine pancreas insufficiency.16, 72
Laparoscopic pancreatectomy represents a new approach to the management of infants with PHHI.67, 73-77 Thus, in diffuse disease a partial pancreatectomy to get the disease milder and manage with postsurgical medical therapy can be an option. This will decrease
postoperative risk of diabetes mellitus and exocrine pancreas insufficiency that need lifelong insulin and pancreatic enzyme replacement therapy. Furthermore, the low risk of intraabdominal adhesions during laparoscopic surgery can give the opportunity of re-operation without surgical complications.
Summary PHHI is one of the most common causes of persistent hypoglycaemia in children. Prompt diagnosis and management of these children is extremely vital to avoid neurological handicap. It is vital for pre-operative histological differentiation of PHHI as the surgical treatment of the two major subgroups i.e diffuse and focal is radically different. Genetic analysis and 18F-DOPA-PET/CT scan allows differentiation between diffuse and focal disease. 18F-DOPA-PET/CT helps in determining the size and location of focal lesions and removal of the focal lesion can cure the patient. For focal lesions in the body or tail of the pancreas, laparoscopic distal pancreatectomy is usually performed. However, partial excision of the head of the pancreas and pancreatico-jejunostomy is required for more proximal focal lesions. The management of the severe diffuse form of the disease still remains a challenge as the treatment options are unsatisfactory with lifelong implications. Near total pancreatectomy is necessary in those children unresponsive to medical therapy, but carries a risk of developing postoperative endocrine and exocrine insufficiency. Laparoscopic near-total pancreatectomy is an option in centres with advanced laparoscopic expertise.
Disclosure Summary: The authors have nothing to disclose
Legends Figure 1: β-cell with recessive inactivating mutations in ABCC8 or KCNJ11 cause continuous membrane depolarization and subsequent calcium influx, which result in unregulated insulin secretion. Figure 2: Histological subtypes of CHI The focal form is localised to a single region of the pancreas whereas diffuse disease affects the whole pancreas. The histology shows marked hyperplasia of the islets in focal disease. Figure 3: Near-total pancreatectomy. The shaded area indicates the remaining pancreas after resection, leaving pancreatic tissue around the common bile duct and along the medial border of the duodenum Figure 4: Focal CHI. Focal PHHI A: Lesion in the body or tail of pancreas (brown circular area) and B: Lesion in the head or neck of pancreas (orange circular area). Surgery for A: Laparoscopic distal pancreatectomy. Surgery for B: Open excision of focal lesion and pancreaticojejunostomy. Figure 5: 18F-DOPA-PET/CT scan of focal lesion located in the head of pancreas Table 1: Summary of treatment and follow up of PHHI patients
Table 2: Summary of the medications used their mechanisms of action and side effects. Diazoxide is the mainstay of therapy for patients with PHHI. However the vast majority patients with defects in the KATP channels will not respond to diazoxide.
Figure 1: Recessive inactivating mutations in ABCC8 or KCNJ11 cause continuous β-cell membrane depolarization and subsequent calcium influx, which result in unregulated insulin secretion.
Mutations in KATP channel
Glucose
SUR1 Kir6.2
Glycolysis
TCA cycle
ATP closes KATP channel
K+
Membrane
ADP ATP
depolarisation
Secretary vesicles Ca2+ causes exocytosis
Insulin
Calcium influx
Figure 2: Histologic subtypes (focal and diffuse) of PHHI (Figure adapted from Hussain et. al. congenital hyperinsulinism. Endocrine surgery in Children)
Figure 3: Near-total pancreatectomy. The shaded area indicates the remaining pancreas after resection, leaving behind pancreatic tissue around the common bile duct and along the medial border of the duodenum66, 68, 69
Figure 4: Focal CHI. A, Lesion in the body or tail of pancreas (brown circular area) and B, Lesion in the head or neck of pancreas (orange circular area).66, 68-71 Surgery for A: Laparoscopic distal pancreatectomy. Surgery for B: Open excision of focal lesion and pancreaticojejunostomy.
A B
Figure 5 : The Standard Uptake Value (SUV) of Fluorine-18-L-3,4-dihydroxyphenylalanine is highest in the head of the pancreas (5.0) compared to the body and tail of the pancreas. At surgery a focal lesion was found located between the superior mesenteric vein and portal vein. (Figure adapted from Hussain et. al. congenital hyperinsulinism. Endocrine surgery in Children)
Table 1. Summary of treatment strategies and follow up for PHHI patients 1. Emergency treatment a. Intravenous glucose infusion (insertion of central venous catheter may be required) b. Glucagon injection c. Frequent feeding 2. Long-term medical treatment i) Diazoxide ii) Chlorothiazide iii) Nifedipine iv) Octreotide and glucagon infusion v) New medicines (long acting octreotide, lanreotide etc.) 3. Arrangement of feeding i. Individualized feeding plan according to fasting tolerance ii. Assessment of protein sensitivity and arrangement of food content iii. Bolus feeding with high calorie and carbohydrate solutions (eg maxijule etc) iv. Overnight continuous intra-gastric feeding v. Corn-starch vi. Anti-reflux medications and solid/semisolid feeds instead of liquids if appropriate 4. Surgical management i. Maintenance of normoglycaemia ii. Differentiation of histologic subtype iii. Lesionectomy for focal disease (laparoscopic or open) iv. Pancreatectomy for diffuse disease a. Partial pancreatectomy in combination with medical therapy b. Subtotal pancreatectomy (removal of up to 95% of pancreas) c. Near-total pancreatectomy (removal of 95 to 98% of pancreas) v. Assessment of postsurgical complications and their management a. Insulin therapy for diabetes mellitus b. Replacement by pancreatic enzymes for exocrine pancreatic insufficiency 5. Other surgical interventions (if required) i. Surgery for gastro-oesophageal reflux ii. PEG gastrostomy 6. Follow up i. Growth ii. Neurological outcome iii. Monitor for side effects of the medications iv. Assessment periodically for fasting tolerance and dose adjustment v. Assessment for postsurgical complications (diabetes and exocrine pancreas insufficiency)
Table 2: Drugs for medical therapy of PHHI
Diazoxide
Route of administrati on
Dose
Oral
5-20 mg/kg/day, in 3 divided doses
Mode of action
Side effects
Bind to SUR1 subunit of KATP channels, opens the channels and inhibits insulin secretion
Common: Water and salt retention, hypertrichosis, loss of appetite
Needs an intact KATP channel activity to work properly
Rare: Cardiac failure, hyperuricaemia, blood dyscrasias (bone marrow suppression, anaemia, eosinophilia etc.), paradoxical hypoglycemia
Chlorothiazid e
Oral
7-10 mg/kg/day, in Prevents fluid 2 divided doses retention, synergistic effects with diazoxide on KATP channels to inhibit insulin secretion
Nifedipine
Oral
0.25-25 mg/kg/day, Inhibits Ca-channels in 2-3 divided of the beta-cell doses membrane
Octreotide
s.c
5-35 µg/kg/day, divided to 3-4 doses or continuous subcutaneous infusion
Activation of SSTR 5 inhibits calcium mobilization and acetylcholine activity, and decreases insulin gene promoter activity, reduces insulin biosynthesis and insulin secretion.
Hyponatraemia, hypokalaemia
Hypotension
Acute: Anorexia, nausea, abdominal discomfort, diarrhoea, drug induced hepatitis, long QT syndrome, tachyphylaxis, necrotizing enterocolitis Long-term: Decreases intestinal motility, bile sludge and gallstone, suppression of pituitary hormones
(Growth hormone, TSH) Glucagon
s.c/i.m bolus or sc/iv infusion
0.02 mg/kg/dose or G-protein coupled 5-10 µg/kg/hour activation of infusion adenylate cylase, increases cAMP, Induces glycogenolysis and gluconeogenesis
Nausea, vomiting, skin rash and rebound hypoglycemia in high doses (>20 µ/kg/hour) due to paradoxical activation of insulin secretion
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