Congenital hyperinsulinism is a medical term referring to a variety of

congenital disorder A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

s in which

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...

is caused by excessive

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

secretion.update 2013 Congenital forms of

hyperinsulinemic hypoglycemia Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin ...

can be transient or persistent, mild or severe. These conditions are present at birth and most become apparent in early infancy. Mild cases can be treated by frequent feedings, more severe cases can be controlled by medications that reduce insulin secretion or effects.

Signs and symptoms

Hypoglycemia in early infancy can cause jitteriness,

lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...

, unresponsiveness, or

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

s. The most severe forms may cause

macrosomia Large for gestational age (LGA) is a term used to describe infants that are born with an abnormally high weight, specifically in the 90th percentile or above, compared to other babies of the same developmental age. Macrosomia is a similar term tha ...

in utero, producing a large birth weight, often accompanied by abnormality of the pancreas. Milder hypoglycemia in infancy causes hunger every few hours, with increasing jitteriness or lethargy. Milder forms have occasionally been detected by investigation of family members of infants with severe forms, adults with the mildest degrees of congenital hyperinsulinism have a decreased tolerance for prolonged fasting. Other presentations are: *

Dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

Intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

* Hypoglycemic

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...

Cardiomegaly Cardiomegaly (sometimes megacardia or megalocardia) is a medical condition in which the heart is enlarged. As such, it is more commonly referred to simply as "having an enlarged heart". It is usually the result of underlying conditions that make t ...

The variable ages of presentations and courses suggest that some forms of congenital hyperinsulinism, especially those involving abnormalities of K_ATP channel function, can worsen or improve with time. The potential harm from hyperinsulinemic hypoglycemia depends on the severity, and duration. Children who have recurrent hyperinsulinemic hypoglycemia in infancy can suffer harm to the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

Cause

The cause of congenital hyperinsulinism has been linked to anomalies in nine genes. The diffuse form of this condition is inherited via the

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

manner (though sometimes in ''

dominant'').

Pathophysiology

In terms of the mechanism of congenital hyperinsulinism one sees that channel trafficking requires K_ATP channels need the shielding of ER retention signal.E282K prevents the K_ATP channel surface expression, the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

( SUR1 subunit) is needed in K_ATP channel mechanism. R1215Q mutations ( ABCC8 gene) affect ADP gating which in turn inhibits K_ATP channel.

Diagnostic

In terms of the investigation of congenital hyperinsulinism, valuable diagnostic information is obtained from a blood sample drawn during 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 In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

s and

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

s provide additional evidence of insulin excess. An additional piece of evidence indicating hyperinsulinism is a usually high requirement for intravenous glucose to maintain adequate glucose levels, the minimum glucose required to maintain a plasma glucose above 70 mg/dl. 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 Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...

at the time of the low glucose. Diagnostic efforts then shift to determining the type- elevated

ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...

levels or abnormal

organic acids An organic acid is an organic compound with acidic properties. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group –COOH. Sulfonic acids, containing the group –SO2OH, are rel ...

can indicate specific, rare types.

Intrauterine growth retardation Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...

and other perinatal problems raise the possibility of transience, while large birthweight suggests one of the more persistent conditions.

Gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

tic screening is now available within a useful time frame for some of the specific conditions. It is 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 Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...

is becoming the most useful imaging technique.

Differential diagnosis

The differential diagnosis of congenital hyperinsulinism is consistent with

PMM2-CDG PMM2 deficiency or PMM2-CDG is a very rare genetic disorder caused by mutations in PMM2. It is an autosomal recessive disorder. A defective copy of the PMM2 gene is the most common cause of a disease called “ congenital disorders of glycosylati ...

, as well as several syndromes. Among other diagnoses, the following are listed: * MPI-CDG * Beckwith-Wiedemann syndrome *

Sotos syndrome Sotos syndrome is a rare genetic disorder characterized by excessive physical growth during the first years of life. Excessive growth often starts in infancy and continues into the early teen years. The disorder may be accompanied by autism, mild ...

* Usher 1 syndromes

Types

Congenital hyperinsulinism has two types, ''diffuse and focal'', as indicated below:

Treatment

In terms of treatment, acute hypoglycemia is 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 certain glucose level. Some of the following measures are often tried:

Corn starch Corn starch, maize starch, or cornflour (British English) is the starch derived from corn (maize) grain. The starch is obtained from the endosperm of the kernel. Corn starch is a common food ingredient, often used to thicken sauces or sou ...

can be used in feeding; unexpected interruptions of continuous feeding regimens can result in sudden hypoglycemia, gastrostomy tube insertion (requires a minor

surgical Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...

procedure) is used for such feeding. Prolonged glucocorticoid use incurs the many unpleasant side effects of

Cushing's syndrome Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, ...

, while

diazoxide Diazoxide, sold under the brand name Proglycem and others, is a medication used to treat low blood sugar due to a number of specific causes. This includes islet cell tumors that cannot be removed and leucine sensitivity. It can also be used in re ...

can cause fluid retention requiring concomitant use of a

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...

, and prolonged use causes

hypertrichosis Hypertrichosis is an abnormal amount of hair growth over the body. The two distinct types of hypertrichosis are generalized hypertrichosis, which occurs over the entire body, and localized hypertrichosis, which is restricted to a certain area. H ...

. Diazoxide works by opening the K_ATP channels of the

beta cell Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...

s. Octreotide must be given by injection several times a day or a subcutaneous pump must be inserted every few days, octreotide can cause

abdominal The abdomen (colloquially called the belly, tummy, midriff, tucky or stomach) is the part of the body between the thorax (chest) and pelvis, in humans and in other vertebrates. The abdomen is the front part of the abdominal segment of the torso. ...

discomfort and responsiveness to octreotide often wanes over time. Glucagon requires continuous intravenous infusion, and has a very short

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...

. Nifedipine is effective only in a minority, and dose is often limited by

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...

. Pancreatectomy (removal of a portion or nearly all of the

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...

) is usually a treatment of last resort when the less-drastic medical measures fail to provide prolonged normal blood sugar levels. For some time, the most common surgical procedure was removal of almost all of the pancreas; this cured some infants but not all. Insulin-dependent

diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

commonly develops, though in many cases it occurs many years after the pancreatectomy. Later it was discovered that a sizeable minority of cases of 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 fewer long-term problems.

History

This condition has been referred to by a variety of names in the past 50 years;

nesidioblastosis Nesidioblastosis is a controversial medical term for hyperinsulinemic hypoglycemia attributed to excessive insulin production by pancreatic beta cells that have an abnormal microscopic appearance. The term was coined in the first half of the 20th c ...

and islet cell adenomatosis were favored in the 1970s,

beta cell dysregulation syndrome Congenital hyperinsulinism is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion.update 2013 Congenital forms of hyperinsulinemic hypoglycemia can be transient or persiste ...

or dysmaturation syndrome in the 1980s, and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) in the 1990s.

References

External links

PubMed
{{DEFAULTSORT:Congenital Hyperinsulinism Disorders of endocrine pancreas Channelopathies Neonatology