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| {{EH}} | | {{Congenital hyperinsulinism}} |
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| ==Overview== | | ==[[Congenital hyperinsulinism overview|Overview]]== |
| '''Congenital hyperinsulinism''' is a medical term referring to a variety of [[congenital disorder]]s in which [[hypoglycemia]] is caused by excessive [[insulin]] secretion. Congenital forms of [[hyperinsulinemic hypoglycemia]] can be transient or persistent, mild or severe. These conditions are present at birth and most become apparent in early infancy. The severe forms can cause obvious problems in the first hour of life, but milder forms may not be detected until adult years.
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| Mild cases can be treated by frequent feedings, more severe cases can be controlled by medications that reduce insulin secretion or effects, and a minority of the most severe cases require surgical removal of part or most of the [[pancreas]] to protect the brain from damage due to recurrent hypoglycemia.
| | ==[[Congenital hyperinsulinism historical perspective|Historical Perspective]]== |
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| ==Terminology== | | ==[[Congenital hyperinsulinism classification|Classification]]== |
| This condition has been referred to by a variety of names in the past 50 years. [[Nesidioblastosis]] and [[islet cell adenomatosis]] were favored in the 1970s, [[beta cell dysregulation syndrome]] or dysmaturation syndrome in the 1980s, and [[persistent hyperinsulinemic hypoglycemia of infancy]] (PHHI) in the 1990s.
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| ==Types of congenital hyperinsulinism== | | ==[[Congenital hyperinsulinism pathophysiology|Pathophysiology]]== |
| *Transient neonatal hyperinsulinism
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| *Focal hyperinsulinism
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| **Paternal [[SUR1]] [[mutation]] with clonal loss of heterozygosity of 11p15
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| **Paternal [[Kir6.2]] mutation with clonal loss of heterozygosity of 11p15
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| *Diffuse hyperinsulinism
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| **[[Autosomal recessive]] forms
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| ***SUR1 mutations
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| ***Kir6.2 mutations
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| **[[Autosomal dominant]] forms
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| ***[[Glucokinase]] gain-of-function mutations
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| ***[[hyperammonemia|Hyperammonemic]] hyperinsulinism (glutamate dehydrogenase gain-of-function mutations)
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| ***[[Short chain acyl coenzyme A dehydrogenase deficiency]]
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| ***[[Carbohydrate-deficient glycoprotein syndrome]]
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| *[[Beckwith-Wiedemann syndrome]] (thought to be due to hyperinsulinism but pathophysiology still uncertain: 11p15 mutation or [[IGF2]] excess)
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| ==Common presentations and natural history== | | ==[[Congenital hyperinsulinism causes|Causes]]== |
| Manifestations of congenital hyperinsulinemic hypoglycemia vary by age and severity of the hypoglycemia. Hypoglycemia in early infancy can cause jitteriness, lethargy, [[cyanosis]], unresponsiveness, [[hypothermia]], or [[seizure]]s. The most severe forms may cause [[macrosomia]] in utero, producing a large-for-gestational-age birth weight, often accompanied by enlargement of the [[heart]] and [[liver]]. Milder hypoglycemia in infancy causes hunger every few hours, with increasing irritability or lethargy if feeding is delayed.
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| Congenital hyperinsulinism often becomes apparent later in the first year of life, sometimes by a failure to tolerate increasing feeding intervals and an inability to sleep through the night. Sometimes an unusual stress like an illness precipitates a severe hypoglycemic episode. | | ==[[Congenital hyperinsulinism differential diagnosis|Differentiating Congenital hyperinsulinism from other Diseases]]== |
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| Milder forms have occasionally been detected by investigation of family members of infants with severe forms. Adults with the mildest degrees of congenital hyperinsulinism may simply have a decreased tolerance for prolonged fasting.
| | ==[[Congenital hyperinsulinism epidemiology and demographics|Epidemiology and Demographics]]== |
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| The variable ages of presentations and courses suggest that some forms of congenital hyperinsulinism, especially those involving abnormalities of K<sub>ATP</sub> channel function, can gradually worsen or improve with time.
| | ==[[Congenital hyperinsulinism risk factors|Risk Factors]]== |
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| The potential harm from hyperinsulinemic hypoglycemia appears to depend on the severity, frequency, and duration. Children who have prolonged or recurrent hyperinsulinemic hypoglycemia in infancy can suffer harm to their [[brain]]s and may be [[developmental delay|developmentally delayed]].
| | ==[[Congenital hyperinsulinism screening|Screening]]== |
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| ==Diagnostic evaluation== | | ==[[Congenital hyperinsulinism natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| When the cause of hypoglycemia is not obvious, the most valuable diagnostic information is obtained from a blood sample drawn during the hypoglycemia. Detectable amounts of insulin during hypoglycemia are abnormal and indicate that hyperinsulinism is likely to be the cause. Inappropriately low levels of [[free fatty acid]]s, [[beta-hydroxybutyrate]] and [[ketone]]s provide additional evidence of insulin excess. If this critical cannot be obtained during an early episode of spontaneous hypoglycemia, a diagnostic fast may be required.
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| An additional piece of evidence indicating hyperinsulinism is an usually high requirement for intravenous glucose to maintain adequate glucose levels. The minimum glucose required to maintain a plasma glucose above 70 mg/dl is referred to as the ''glucose infusion rate''. A GIR above 8 mg/kg/minute in infancy suggests hyperinsulinism. A third form of evidence suggesting hyperinsulinism is a rise of the glucose level after injection of [[glucagon]] at the time of the low glucose.
| | ==Diagnosis== |
| | | [[Congenital hyperinsulinism history and symptoms| History and Symptoms]] | [[Congenital hyperinsulinism physical examination | Physical Examination]] | [[Congenital hyperinsulinism laboratory findings|Laboratory Findings]] | [[Congenital hyperinsulinism x ray| X Ray]] | [[Congenital hyperinsulinism CT|CT]] | [[Congenital hyperinsulinism MRI|MRI]] | [[Congenital hyperinsulinism ultrasound|Ultrasound]] | [[Congenital hyperinsulinism other imaging findings|Other Imaging Findings]] | [[Congenital hyperinsulinism other diagnostic studies|Other Diagnostic Studies]] |
| Once the evidence indicates hyperinsulinism, the diagnostic efforts shift to determining the type. Elevated [[ammonia]] levels or abnormal [[organic aciduria|organic acids]] can indicate specific, rare types. [[Intrauterine growth retardation]] and other perinatal problems raise the possibility of transience, while large birthweight suggests one of the more persistent conditions. Evidence for specific type can include responsiveness to some of the therapeutic measures. [[gene|Genetic]] screening is now available within a useful time frame for some of the specific conditions.
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| It is usually worthwhile to identify the minority of severe cases with focal forms of hyperinsulinism because these can be completely cured by partial pancreatectomy. A variety of pre-operative diagnostic procedures have been investigated but none has been established as infallibly reliable. [[Positron emission tomography]] (PET scanning) is becoming the most useful imaging technique and usually indicates whether the entire pancreas is producing too much insulin or whether a focal area is to blame.
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| ==Treatment== | | ==Treatment== |
| Acute hypoglycemia is immediately reversed by raising the blood glucose, but in most forms of congenital hyperinsulinism hypoglycemia recurs and the therapeutic effort is directed toward preventing falls and maintaining a glucose above 70 mg/dl (3.9 mM). Some of the following measures are often tried:
| | [[Congenital hyperinsulinism medical therapy|Medical Therapy]] | [[Congenital hyperinsulinism surgery|Surgery]] | [[Congenital hyperinsulinism primary prevention|Primary Prevention]] | [[Congenital hyperinsulinism secondary prevention|Secondary Prevention]] | [[Congenital hyperinsulinism cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Congenital hyperinsulinism future or investigational therapies|Future or Investigational Therapies]] |
| *shorter feeding interval (every 2 hours)
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| *increased calorie density of formula (usually 24 calories per ounce instead of 20)
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| *continuous feeding with [[infant formula|formula]] through a [[nasogastric tube]] or [[gastrostomy]], sometimes with added corn starch
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| *continuous intravenous [[dextrose]]
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| *[[hydrocortisone]] or other [[glucocorticoid]]
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| *[[diazoxide]] by mouth
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| *[[octreotide]] (a [[somatostatin]] analog) by subcutaneous injection or infusion
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| *[[glucagon]] by continuous intravenous infusion
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| *[[nifedipine]] or other [[calcium channel blocker]]
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| *partial [[pancreatectomy]]
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| Each treatment has its limitations and disadvantages or hazards. Many of the treatments do not effectively maintain a satisfactory blood glucose in the more severe cases. Many of the treatments aggravate the poor feeding behavior that often accompanies severe congenital hyperinsulinism. It is hard for parents to continue frequent feedings for many months. Increased calories and corn starch may produce excessive weight gain. Unexpected interruptions of continuous feeding regimens can result in sudden, severe hypoglycemia. Insertion and maintenance of nasogastric tubes is distasteful to parents. Gastrostomy tube insertion requires a minor [[surgery|surgical]] procedure. Prolonged glucocorticoid use incurs the many unpleasant side effects of [[Cushing's syndrome]]. Diazoxide can cause fluid retention requiring concomitant use of a [[diuretic]], and prolonged use causes [[hypertrichosis]]. Diazoxide works by opening the K<sub>ATP</sub> channels of the [[beta cell]]s, and many of the Kir and SUR mutations are unresponsive. Octreotide must be given by injection several times a day or a subcutaneous pump must be inserted every few days. Octreotide can cause [[abdomen|abdominal]] discomfort and responsiveness to octreotide often wanes over time. Glucagon requires continuous intravenous infusion, incurring the [[infection]] and [[blood clot]] hazards of prolonged central venous lines. Nifedipine is effective only in a minority, and dose is often limited by [[hypotension]].
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| Pancreatectomy (removal of a portion or nearly all of the [[pancreas]]) is usually a treatment of last resort when the simpler medical measures fail to provide prolonged normal blood sugar levels. For many decades, the most common surgical procedure was removal of about 95% of the pancreas. This cured some infants but not all, and some needed second procedures to remove even the last remnants. Insulin-dependent [[diabetes mellitus]] commonly develops, though in many cases it occurs many years after the pancreatectomy.
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| In the early 1990s it was discovered that a sizeable minority of cases of Kir and SUR mutations were focal, involving overproduction of insulin by only a portion of the pancreas. These cases can be cured by removing much less of the pancreas, resulting in excellent outcomes with no long-term problems. The initial pancreatectomy became a prolonged process of repeated [[microscope|microscopic]] examination of small pieces removed from various parts of the pancreas while the infant was under [[anesthesia]] in the operating room, with an experienced surgeon and [[pathology|pathologist]] attempting to identify a focal region of overactive cells which could be completely removed.
| | ==Case Studies== |
| | [[Congenital hyperinsulinism case study one|Case#1]] |
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| The relative rarity of this condition and the difficulty of both diagnosis and treatment has resulted in only a few centers around the world developing the expertise to achieve optimal surgical outcomes for these infants: the [[Children's Hospital of Philadelphia]], the [[Great Ormond Street Hospital|Great Ormond Street Hospital for Children]] in London, as well as centers in Paris and Israel.
| | ==Related Chapters== |
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| ==See Also== | |
| [http://www.chop.edu/consumer/jsp/division/service.jsp?id=47690 Congenital Hyperinsulinism Center] | | [http://www.chop.edu/consumer/jsp/division/service.jsp?id=47690 Congenital Hyperinsulinism Center] |
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| [http://www.sur1.org/ Sur1 Hyperinsulinism] | | [http://www.sur1.org/ Sur1 Hyperinsulinism] |
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| {{SIB}}
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| [[Category:Genetic disorders]] | | [[Category:Genetic disorders]] |