Congenital hyperinsulinism

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Classification according to ICD-10
E16.1 other hypoglycaemia
ICD-10 online (WHO version 2019)

Congenital hyperinsulinism (HI) is a rare congenital disorder of the pancreas , which is characterized by increased insulin secretion and the resulting low blood sugar ( hypoglycaemia ). HI is one of the most common causes of hypoglycaemia in newborns and young children and a risk factor for the development of permanent brain damage .

Symptoms of HI range from increased hunger, apathy , paleness, nervousness to seizures , coma and death of the person concerned. Therefore, early diagnosis and intervention are required to prevent permanent neurological damage. Some cases of HI are manifested in increased birth weight.

The causes of HI are mostly due to genetic defects in the regulation of the blood sugar sensor system of the β cells of the islets of Langerhans in the pancreas . HI can be divided histologically into diffuse or focal forms. While all insulin- producing β-cells in the pancreas are affected in the diffuse form , in the focal form there is a somatic mutation which is limited to individual, adenoma-like sections within the pancreas.

Treatment for HI depends on the histological form and genetic cause. Lighter cases of HI can be controlled with an adapted diet, while more severe cases must be treated with medication. In severe cases, can resection of a large part of the pancreas be needed. In the case of the focal form of HI, surgery can often be used to remove the affected tissue from the pancreas in a targeted manner and thus permanently cure the disease.

HI is a rare condition with an incidence of about 1 in 40,000 in northern Europe. In parts of the world with a high proportion of consanguinity , however, the incidence is estimated to be significantly higher at 1: 2500.

Mechanisms and Causes

HI is caused by genetic defects in the regulation of insulin release by the β cells in the islets of Langerhans in the pancreas. This leads to an inappropriately high insulin secretion with subsequent hypoglycemia .

Three types of HI are histologically distinguished: diffuse, focal and atypical HI. HI can also occur in a transient form, which, regardless of the cause, heals independently within the first two months of life. In the diffuse form of HI, all islets of Langerhans in the pancreas are affected by a gene mutation .

In focal HI, all cells are affected by a heterozygous mutation that alone would not be sufficient to cause HI. Only when a second, somatic mutation changes the healthy allele pathologically, individual, adenoma-like sections develop within the pancreas, in which insulin secretion is stimulated.

Affected genes are, for example, the ATP-sensitive potassium channel ( ABCC8 and KCNJ11 ), glutamate dehydrogenase ( GLUD1 ), glucokinase ( GCK ), short-chain 3-hydroxyacyl-CoA dehydrogenase ( HADH ), transcription factors ( HNF1A , HNF4A ) and others ( SLC16A1 , UCP1 , PGM1 etc.).

ATP-sensitive potassium channel ( ABCC8 , KCNJ11 )

ABCC8 and KCNJ11 code for the two subunits of the ATP-sensitive potassium channel , which controls the lowering of the membrane potential in the regulation of insulin secretion . Recessive mutations in ABCC8 and KCNJ11 are the most common cause of HI. Most of these genetic defects lead to a reduction or loss of the function of the ATP-regulated potassium channel. Dominant mutations in ABCC8 and KCNJ11 also lead to a reduction in the function of the ATP-sensitive potassium channel , although this is often less pronounced.

Glutamate dehydrogenase ( GLUD1 )

Dominant mutations in GLUD1 are the second leading cause of HI. Those affected suffer from a subtype of HI, which is characterized by hyperammonaemia . GLUD1 codes for the mitochondrial enzyme glutamate dehydrogenase (GDH). GDH converts glutamate into α-ketoglutarate , which is further metabolized in the citric acid cycle . This leads to the production of ATP, which stimulates the closure of the ATP-sensitive potassium channels and then insulin secretion .

The activity of GDH is influenced by various factors. For example, the amino acid leucine can increase the activity of GDH, while GTP, a nucleoside triphosphate , reduces the activity. The latter can be restricted by a mutation in GLUD1 . This promotes the stimulation of the activity of GDH by leucine. Therefore, high protein meals can lead to hypoglycemia in those affected.

Glucokinase ( GCK )

Glucokinase is the glucose sensor of the pancreatic β-cells. Glucokinase phosphorylates glucose to glucose-6-phosphate, one of the first steps in the blood sugar sensing system . Dominant mutations , which increase the affinity of glucokinase for glucose, lower the body's own guideline value for euglycaemia, whereby β-cells are stimulated to release insulin even at low blood sugar levels .

Short-chain 3-hydroxyacyl-CoA dehydrogenase ( HADH )

Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) is a β-oxidation enzyme . Recessive mutations that lead to the loss of this enzyme are a rare cause of HI. How SCHAD regulates insulin secretion and why the loss of the enzyme causes HI are not yet fully understood. A likely cause could be the interaction of SCHAD with GDH. A function of SCHAD may be to inhibit GDH activity. Similar to mutations in GLUD1 , patients with recessive mutations in HADH are prone to hypoglycemia after protein-rich meals. A characteristic feature of this form of HI are increased levels of 3-hydroxyglutarate in the urine and hydroxybutyrylcarnitine in the blood of those affected.

diagnosis

The first sign of HI is a diagnosis of hypoglycemia . This is when the blood sugar level falls below 50 mg / dL (2.8 mmol / L). In addition to HI, hypoglycemia in children can have various causes. Clinical evidence, laboratory tests, and molecular genetic analyzes are therefore crucial for a diagnosis of HI.

Clinical Notes

The symptoms of HI and hypoglycaemia can have different causes. In addition to HI, defects in the body's own production ( glycogen synthesis ) or the release ( glycogenolysis ) of glucose by the liver can lead to hypoglycaemia . A glucagon test can be used to rule out this. The hormone glucagon stimulates glycogen synthesis and glycogenolysis and thus ensures an increase in blood sugar levels during hypoglycemia . If these processes are disturbed, glucagon does not work and HI can be excluded. If the blood sugar level rises after a dose of glucagon, increased insulin secretion is a more likely cause of hypoglycaemia.

Laboratory tests

In the case of HI, an increased insulin level can often be determined in the blood during hypoglycaemia. However, since an increased insulin value cannot always be clearly determined, blood samples are also examined for the amount of free fatty acids and ketone bodies . One of the functions of insulin is to suppress fat burning . Therefore, less fat is metabolized in HI even during hypoglycaemia, which leads to a reduction in free fatty acids and ketone bodies in the blood. These tests are also important to rule out that the cause of the hypoglycemia is a defect in lipid metabolism, which reduces the amount of fatty acids and ketone bodies regardless of the effects of the insulin.

Molecular genetic analysis

Since HI is usually caused by a specific gene mutation , this can be determined by genetic testing. If none of the known mutations is found, the cause of the HI may be a somatic mutation or, in rare cases, an as yet unknown mutation. The result of the molecular genetic analysis is often decisive for the further diagnosis and type of treatment.

treatment

The aim of treatment for HI is to optimally control blood sugar levels . This can be achieved through medication, surgery (for focal HI and in rare cases for diffuse HI) and diet.

Short-term and emergency treatment

In acute cases it is necessary to keep the blood sugar level above 3.5 mmol / L to prevent neurological complications. This can be done by giving a glucose solution orally or intravenously. In addition to glucose, glucagon can also be used to stabilize blood sugar.

Long-term drug treatment

Long-term treatment depends on the underlying gene mutation and must therefore be individually adapted. Patients with an intact ATP-sensitive potassium channel can be treated with diazoxide , an agonist of the ATP-sensitive potassium channel . Diazoxide works by attaching to and opening the potassium channel . This results in a decrease in insulin secretion . In HI patients with recessive and some dominant mutations of the ATP-sensitive potassium channel , diazoxide often does not work and other therapies must be used.

In addition to diazoxide, octreotide and other somatostatin analogues can also be used for therapy. These inhibit insulin secretion by mimicking the effects of the hormone somatostatin.

nutrition

Diet is very important in the treatment of HI. Fluctuating blood sugar levels and impaired eating behavior (refusal to eat, cravings, vomiting) often go hand in hand with one another. In addition, many sufferers have a low tolerance to longer fasting times. Eating more often can help keep blood sugar stable, but in many cases it can be difficult to implement. Tube feeding may therefore be necessary, especially in infancy to childhood . In addition, multiple sugars such as maltodextrin can be added to normal food or a high-calorie diet.

Web links

Individual evidence

  1. ↑ a b c d e f g h i j H. Demirbilek, K. Hussain: Congenital Hyperinsulinism: Diagnosis and Treatment Update. In: Journal of clinical research in pediatric endocrinology. Volume 9, Suppl 2 December 2017, pp. 69-87, doi : 10.4274 / jcrpe.2017.S007 , PMID 29280746 , PMC 5790328 (free full text) (review).
  2. Jump up ↑ JB Arnoux, V. Verkarre, C. Saint-Martin, F. Montravers, A. Brassier, V. Valayannopoulos, F. Brunelle, JC Fournet, JJ Robert, Y. Aigrain, C. Bellanné-Chantelot, P. de Lonlay : Congenital hyperinsulinism: current trends in diagnosis and therapy. In: Orphanet Journal of Rare Diseases. Volume 6, October 2011, p. 63, doi : 10.1186 / 1750-1172-6-63 , PMID 21967988 , PMC 3199232 (free full text) (review).
  3. ↑ a b ABCC8 - ATP-binding cassette sub-family C member 8 - Homo sapiens (Human) - ABCC8 gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  4. ↑ a b KCNJ11 - ATP-sensitive inward rectifier potassium channel 11 - Homo sapiens (Human) - KCNJ11 gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  5. ↑ a b GLUD1 - Glutamate dehydrogenase 1, mitochondrial precursor - Homo sapiens (Human) - GLUD1 gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  6. ↑ a b GCK - Glucokinase - Homo sapiens (Human) - GCK gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  7. ↑ a b HADH - Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial precursor - Homo sapiens (Human) - HADH gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  8. ↑ HNF1A - Hepatocyte nuclear factor 1-alpha - Homo sapiens (human) - HNF1A gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  9. ↑ HNF4A - Hepatocyte nuclear factor 4-alpha - Homo sapiens (human) - HNF4A gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  10. ↑ SLC16A1 - Monocarboxylate transporter 1 - Homo sapiens (Human) - SLC16A1 gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  11. ↑ UCP1 - Mitochondrial brown fat uncoupling protein 1 - Homo sapiens (human) - UCP1 gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  12. ↑ PGM1 - Phosphoglucomutase-1 - Homo sapiens (Human) - PGM1 gene & protein. In: uniprot.org. Retrieved October 18, 2018 .
  13. ↑ a b c d C. James, RR Kapoor, D. Ismail, K. Hussain: The genetic basis of congenital hyperinsulinism. In: Journal of medical genetics. Volume 46, Number 5, May 2009, pp. 289-299, doi : 10.1136 / jmg.2008.064337 , PMID 19254908 (review).
  14. ↑ CA Stanley, YK Lieu, BY Hsu, AB Burlina, CR Greenberg, NJ Hopwood, K. Perlman, BH Rich, E. Zammarchi, M. Poncz: Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. In: The New England Journal of Medicine . Volume 338, Number 19, May 1998, pp. 1352-1357, doi : 10.1056 / NEJM199805073381904 , PMID 9571255 .
  15. ^ A b C. A. Stanley: Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders. In: The Journal of Clinical Endocrinology and Metabolism . Volume 101, number 3, March 2016, pp. 815-826, doi : 10.1210 / jc.2015-3651 , PMID 26908106 , PMC 4803157 (free full text) (review).
  16. ↑ CA Stanley: Hyperinsulinism / hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. In: Molecular Genetics and Metabolism. Volume 81 Suppl 1, April 2004, pp. S45-S51, doi : 10.1016 / j.ymgme.2003.10.013 , PMID 15050973 (review).
  17. ^ A b S. Chandran, F. Yap, K. Hussain: Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia. In: World J Diabetes. 5, 2014, pp. 666-677, PMID 25317244 PMC 4138590 (free full text).
  18. ↑ a b P. T. Clayton, S. Eaton, A. Aynsley-Green, M. Edginton, K. Hussain, S. Krywawych, V. Datta, HE Malingre, R. Berger, IE van den Berg: Hyperinsulinism in short-chain L. -3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. In: The Journal of clinical investigation. Volume 108, number 3, August 2001, pp. 457-465, doi : 10.1172 / JCI11294 , PMID 11489939 , PMC 209352 (free full text).
  19. ↑ a b A. Molven, GE Matre, M. Duran, RJ Wanders, U. Rishaug, PR Njølstad, E. Jellum, O. Søvik: Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. In: Diabetes. Volume 53, Number 1, January 2004, pp. 221-227, PMID 14693719 .
  20. ↑ C. Li, P. Chen, A. Palladino, S. Narayan, LK Russell, S. Sayed, G. Xiong, J. Chen, D. Stokes, YM Butt, PM Jones, HW Collins, NA Cohen, AS Cohen , I. Nissim, TJ Smith, AW Strauss, FM Matschinsky, MJ Bennett, CA Stanley: Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. In: Journal of Biological Chemistry . Volume 285, Number 41, October 2010, pp. 31806-31818, doi : 10.1074 / jbc.M110.123638 , PMID 20670938 , PMC 2951252 (free full text).
  21. ↑ AJ Heslegrave, K. Hussain: Novel insights into fatty acid oxidation, amino acid metabolism, and insulin secretion from studying patients with loss of function mutations in 3-hydroxyacyl-CoA dehydrogenase. In: The Journal of Clinical Endocrinology and Metabolism . Volume 98, Number 2, February 2013, pp. 496-501, doi : 10.1210 / jc.2012-3134 , PMID 23253615 (review).