1 Introduction
2 normal blood glucose and hypoglycemia
2.1 Definition of normal blood glucose
2.2 Causes of hypoglycemia
Hyperinsulinism | Transient Infant of diabetic mother Perinatal asphyxia Rhesus hemolytic disease Intrauterine growth restriction HNF4A/HNF1A Congenital ABCC8/ KCNJ11/ GCK/ GDH/ HADH/ HNF4A/ HNF1A/ UCP2/ SLC16A1/PMM2/HK1/PGM1/FOXA2/CACNA1D/EIF2S3 Others Post-prandial hyperinsulinemic hypoglycemia Insulinoma Munchausen’s by proxy Exercise induced hyperinsulinemic hypoglycemia |
Hypoinsulinemic hypoglycemia | Activating AKT2 mutations |
Counter-regulatory hormone deficiency | Growth hormone deficiency Adrenal insufficiency |
Fatty acid oxidation disorders | Medium chain acyl-CoA dehydrogenase deficiency Long chain acyl-CoA dehydrogenase deficiency Short chain acyl-CoA dehydrogenase deficiency |
Defects in ketone body synthesis/ utilization | HMG CoA synthase deficiency HMG CoA lyase deficiency |
Carnitine deficiency (primary and secondary) | Carnitine palmitoyl transferase deficiency (CPT 1 and 2), Carnitine deficiency |
Gluconeogenic disorders | Fructose-1, 6-bisphosphatase deficiency, Phosphoenolpyruvate carboxykinase (PEPCK) deficiency Pyruvate carboxylase deficiency |
Glycogen storage disorders | Glucose-6-phosphatase deficiency Amylo 1–6 glucosidase deficiency Glycogen synthase deficiency |
Defects in glucose transport | GLUT 1/2/3 transporters defects |
Other metabolic conditions | Galactosemia, Fructosemia, Tyrosinemia, Glutaric aciduria type 2, Maple syrup urine disease, Propionic academia Adenosine kinase deficiency Mitochondrial respiratory chain disease |
3 HYPERINSULINEMIC hypoglycemia (HH)
4 Causes of HH
4.1 Transient forms of HH
4.2 Permanent form of HH
4.2.1 Molecular basis of CHH
4.3 Other forms
4.3.1 Postprandial forms of HH
4.3.2 Other causes of HH
4.3.3 Syndromes associated with HH
SYNDROME NAME | GENETIC ETIOLOGY gene (location) | CLINICAL CHARACTERISTICS |
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Pre- and postnatal overgrowth (Macrosomia) | ||
Beckwith-Wiedemann | (11p15) | Macroglossia, abdominal wall defects, ear lobe pits/ creases, hemihypertrophy, tumor risk |
Sotos | NSD1 (5q35) | Macrocephaly, frontal bossing, pointed chin, developmental delay, tumor risk |
Simpson-Golabi-Behmel | Coarse facial features, broad feet, polydactyly, cryptorchidism, hepatomegaly, tumor risk | |
Perlman | DIS3L2 (2q37) | Inverted V-shaped upper lip, prominent forehead, developmental delay, hypotonia, tumor risk |
Postnatal growth failure (short stature) | ||
Kabuki | KMT2D (12q13), KDM6A (Xp11.3) | Arched eyebrows, long eyelashes, developmental delay, fetal finger pads, scoliosis, heart defects, hypotonia |
Costello | HRAS (11p15) | Deep palmar/plantar creases, developmental delay coarse facial features, heart abnormalities, papillomas, tumor risk |
Chromosomal abnormality | ||
Mosaic Turner | (Loss of X in some cells) | Milder Turner syndrome phenotype (short stature, coarctation of aorta, gonadal dysgenesis) |
Patau | Trisomy 13 | Developmental delay, microphthalmia, heart & neural defects |
Congenital disorders of glycosylation | ||
Types 1a, 1b, and 1d | Developmental delay, hypotonia, growth failure | |
Contiguous gene deletion affecting the ABCC8 gene | ||
Usher | 11 genes | Hearing loss, visual impairment |
Abnormalities in calcium homoeostasis | ||
Timothy | CACNA1C (12p13.33) | Long QT syndrome, syndactyly, developmental delay, immune deficiency |
Insulin receptor mutation: | ||
Insulin resistance syndrome (leprechaunism) | INS (19p13) | Hypo- and hyperglycemia, pre- and postnatal growth restriction, elfin-like features, hirsutism |
Other Syndromes: | ||
Congenital central hypoventilation syndrome | PHOX2B (4p13) | Central hypoventilation, “box-shaped” face, neurocristopathies (Hirschsprung disease, tumor risk) |
5 Pathophysiology of HH - histological subtypes
5.1 Focal form of CHH (F-CHH)
5.2 Diffuse form of CHH (D-CHH)
5.3 Atypical forms of HH
6 Clinical presentation of HH
7 Diagnostic investigations of HH
7.1 Biochemistry
Serum analyte | Result in patients with HH |
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Blood glucose < 3.0 mmol/l (54 mg/dl) and: | |
Insulin | Detectable |
C-peptide | Detectable (≥0.5 ng/mL¥) |
Free fatty acids | Low or suppressed (<1.5 mmol/l* or < 1.7 mmol/l¥) |
Ketone bodies | Low or suppressed (3-β-hydroxybutyrate <2 mmol/l* or < 1.8 mmol/l¥) |
IGFBP-1 | Low (≤110 ng/mL¥) as insulin negatively regulates IGFBP-1 expression |
Ammonia | Normal. Can be raised in HI/HA syndrome |
Hydroxybutyrylcarnitine | Normal. Raised in HH due to HADH mutation |
Cortisol, Growth hormone | Raised. Generally Cortisol >20 μg/dL [500 nmol/L]; growth hormone >7 ng/mL - younger children might have poor counter-regulatory response |
Amino acids and urine organic acids | Normal. Leucine, isoleucine and valine may be suppressed in HH |
Proinsulin | >20 pmol/l |
Additional information when diagnosis of HH uncertain: | |
Glucose infusion rate | >8 mg/kg/min to achieve euglycemia |
Im or iv glucagon administration or sc octreotide administration | >1.5 mmol/L or 27 mg/dl (Positive glycemic response) |
7.1.1 Protein load test
7.1.2 Oral glucose tolerance test / mixed meal test
7.1.3 Exercise test and pyruvate load
7.1.4 Fructose load test
7.1.5 The role of real-time continuous glucose monitoring (CGM)
7.2 Imaging
7.2.1 Recent advances in diagnostic imaging of HH
7.2.2 Imaging for insulinoma
8 Management of HH
Medication (route of administration) | Total daily dose | Action mechanism | Side effects | |
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Standard drugs | Diazoxide (enteral) | 5-20 mg/kg/day (divided in 3 doses) | Binds to the SUR1 subunit of intact KATP channels, opening the channel and inhibiting insulin release | Common: Fluid and sodium retention, hypertrichosis, anorexia. Rare: Cardiac failure, pulmonary hypertension**, blood dyscrasia, hyperuricemia, paradoxical hypoglycemia |
Chlorothiazide (enteral) | 7-10 mg/kg/day (divided in 2 doses) | Synergy with diazoxide over KATP channels inhibiting insulin secretion. Prevents fluid overload | Hyponatremia, hypokalemia | |
Glucagon (sc/im bolus; sc/iv infusion) | Bolus: 0.02 mg/kg/dose Infusion: 2.5–10 mcg/kg/h | Stimulates glycogenolysis, gluconeogenesis, ketogenesis, lipolysis | Skin rash, vomiting. Paradoxical rebound hipoglycemia if dose >20mcg/kg/h (high dose stimulates insulin release) | |
Octreotide (sc) | 5–40 mcg/kg/day (divided in 3–4 doses or continuous infusion) | Activation of SSTR-2 and SSTR-5. Stabilisation of KATP channel, reduces calcium entry in β-cell, inhibition of insulin secretion. Inhibitition of INS promoter. | Acute: Abdominal discomfort, vomiting, diarrhea, anorexia, hepatitis, transaminasemia, long QT syndrome, necrotizing enterocolitis, tachyphylaxis. Long-term: Cholelithiasis, intestinal hypomobility, suppression of GH and TSH | |
Nifedipine (enteral) | 0.25–2.5 mg/kg/day (divided in 2–3 doses) | Blockage of β-cell calcium channel activity, leading to inhibition of insulin exocytosis | Hypotension | |
Acarbose (enteral) | 6.25–300 mg/day (divided in 3 doses – before main meals) | Inhibits intestinal α-glucosidase (cleaves polysaccharides to monosaccharides) | Intestinal discomfort, diarrhoea, flatulence, raised transaminases | |
Novel drugs | Lanreotide and long-acting octreotide (deep sc or im) | 30–60 (max 120*) mg/dose (every 4 weeks) | Like octreotide. High affinity for SSTR 2 & 5, and reduced affinity for SSTR 1, 3 & 4 | Same as octreotide. Pain at injection site. No long-term data available yet. |
mTOR inhibitors (enteral) | Starting dose: 1 mg/m2/day (divided in 2 doses). Adjust dose aiming for blood concentrations 5-15 ng/ml | Inhibits mTOR complex 1. Inhibits β-cell proliferation and insulin secretion. Posible induction of peripheral insulin resistance | Immune suppression, hyperlipidemia, hypertransaminasemia, mucositis, thrombocytosis |
9 Current medical management
9.1 Acute management of hypoglycemia
9.2 Long-term pharmacological agents
9.2.1 Medical management of diazoxide unresponsive D-CHH
10 Novel medical therapies
10.1 Long-acting somatostatin analogues
10.2 mTOR inhibitors
11 Potential novel therapies – The future
11.1 GLP-1 antagonists
11.2 Pharmacological trafficking chaperones
11.3 Glucagon – New formulations and delivery
12 Surgical management
12.1 Surgery for F-CHH
12.2 Surgery for D-CHH
12.3 Surgery for insulinoma
13 HH monitoring and follow up
14 Transition into adult service
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heightened concerns about peer relationships and social interactions,
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frustration and fatigue from the management of a chronic illness,
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incomplete knowledge and understanding of chronic disease management,
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inclination towards risk-taking and
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difficulties in the transition to self-management.
14.1 Aims of the transition service
Medical Issue | Support / Intervention needed |
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Confirmed mutation causing HH | |
Symptom control | • Exploring precipitants • Dietary interventions and advice • Need for medical treatment e.g. diazoxide, calcium channel blockers, somatostatin analogues. • Accessing appropriate technology e.g. real-time CGM, where appropriate |
Risk of diabetes | • Aware of diabetes symptoms • Annual glucose checks • Understands the risk of diabetes |
Managing diabetes in non-pancreatectomized individuals | • Establishing type of diabetes • Impact of underlying genetic mutation • Measuring endogenous insulin production to determine if insulin needed. |
Managing diabetes in pancreatectomized individuals | • Diagnosing and treating insulin-deficient diabetes in these individuals early on • Ensuring life-long insulin and clearly aware of diagnosis • Managing concurrent exocrine failure • Loss of glucagon may also contribute to problematic hypoglycemia • Ensuring access to appropriate diabetes technologies e.g. insulin pumps and continuous glucose monitoring |
Impaired hypoglycemia awareness | • Checking individuals know the symptoms of hypoglycemia • Assessing awareness of hypoglycemia using validated scores e.g. Clarke or GOLD score. • Considering adjunctive use of monitoring technologies such as real-time continuous glucose monitoring in those with hypoglycemia unawareness. |
No mutation identified (in addition to above) | |
Exploring a genetic diagnosis | • Ensuring panel of all genes tested • Undertaking whole exome or whole genome sequencing studies to identify novel genes • Re-characterizing type of hyperinsulinism and considering alternative diagnosis |
Counseling around diagnostic uncertainty | • Ensure adequately knowledgeable about their condition • Symptom control • Need to continue medical therapy • Pregnancy |
14.2 Developing the HH transition pathways
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Planning a service: Young people should be involved in designing the service.
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Planning for transition, which should be appropriately timed for the individual.
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Before Transition: young adults should have joint clinics with the pediatric and adult teams.