Crigler-Najjar syndrome
Encyclopedia
Crigler-Najjar Syndrome or CNS is a rare disorder affecting the metabolism
of bilirubin
, a chemical formed from the breakdown of blood
. The disorder results in an inherited form of non-hemolytic
jaundice
, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants
.
This syndrome is divided type I and type II, with the latter sometimes called Arias syndrome. These two types, along with Gilbert's syndrome
, Dubin-Johnson syndrome
, and Rotor syndrome
, make up the five known hereditary
defects in bilirubin metabolism. Unlike Gilbert's syndrome, only a few hundred cases of CNS are known.
increases the risk of this condition (other rare diseases may be present). Inheritance
is autosomal recessive
.
Intense jaundice appears in the first days of life and persists thereafter. Type 1 is characterised by a serum
bilirubin usually above 345 µmol/L (310–755) (whereas the reference range
for total bilirubin is 2–14 μmol/L).
No UGT1A1
(UDP glucuronosyltransferase 1 family, polypeptide A1) expression can be detected in the hepatic tissue. Hence, there is no response to treatment with phenobarbital
(which causes enzyme induction
). Most patients (type IA) have a mutation in one of the common exons (2 to 5), and have difficulties conjugating several additional substrates (several drugs and xenobiotics). A smaller percentage of patients (type IB) have mutations limited to the bilirubin-specific A1 exon
; their conjugation defect is mostly restricted to bilirubin itself.
Before the availability of phototherapy, these children died of kernicterus
(bilirubin encephalopathy) or survived until early adulthood with clear neurological impairment. Today, therapy includes
may develop in the presence of sepsis
, hypoxia
, hypoglycemia
, hypothyroidism
, hypertrophic pyloric stenosis, galactosemia
, fructosemia, and so on.
Hyperbilirubinemia of the unconjugated type may be caused by
In Crigler–Najjar syndrome and Gilbert syndrome, routine liver function tests
are normal, and hepatic histology
usually is, too. There is no evidence for hemolysis
. Drug-induced case typically regress after discontinuation of the substance. Physiological neonatal jaundice
may peak at 85–170 µmol/L and decline to normal adult concentrations within two weeks. Prematurity results in higher levels.
transplantation.
The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since there is only one enzyme
working improperly, gene therapy
for Crigler Najjar is a theoretical option which is being investigated.
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
, a chemical formed from the breakdown of blood
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
. The disorder results in an inherited form of non-hemolytic
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants
Kernicterus
Kernicterus is damage to the brain centers of infants caused by increased levels of unconjugated bilirubin. This may be due to several underlying pathologic processes. Newborn babies are often polycythemic. When they break down the erythrocytes, one of the byproducts is bilirubin, which circulates...
.
This syndrome is divided type I and type II, with the latter sometimes called Arias syndrome. These two types, along with Gilbert's syndrome
Gilbert's syndrome
Gilbert's syndrome , often shortened to GS, also called Gilbert-Meulengracht syndrome, is the most common hereditary cause of increased bilirubin and is found in up to 5% of the population...
, Dubin-Johnson syndrome
Dubin-Johnson syndrome
Dubin–Johnson syndrome is an autosomal recessive disorder that causes an increase of conjugated bilirubin in the serum without elevation of liver enzymes . This condition is associated with a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile, and is similar to...
, and Rotor syndrome
Rotor syndrome
Rotor syndrome, also called Rotor type hyperbilirubinemia, is a rare, relatively benign autosomal recessive bilirubin disorder of unknown origin...
, make up the five known hereditary
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
defects in bilirubin metabolism. Unlike Gilbert's syndrome, only a few hundred cases of CNS are known.
Crigler-Najjar syndrome, type I
This is a very rare disease (estimated at 0.6–1.0 per million live births), and consanguinityConsanguinity
Consanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...
increases the risk of this condition (other rare diseases may be present). Inheritance
Inheritance
Inheritance is the practice of passing on property, titles, debts, rights and obligations upon the death of an individual. It has long played an important role in human societies...
is autosomal recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
.
Intense jaundice appears in the first days of life and persists thereafter. Type 1 is characterised by a serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
bilirubin usually above 345 µmol/L (310–755) (whereas the reference range
Reference range
In health-related fields, a reference range or reference interval usually describes the variations of a measurement or value in healthy individuals...
for total bilirubin is 2–14 μmol/L).
No UGT1A1
UGT1A1
UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the UGT1A1 gene.UGT-1A is a uridine diphosphate glucuronyltransferase , an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and...
(UDP glucuronosyltransferase 1 family, polypeptide A1) expression can be detected in the hepatic tissue. Hence, there is no response to treatment with phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
(which causes enzyme induction
Enzyme induction and inhibition
Enzyme induction is a process in which a molecule induces the expression of an enzyme.Enzyme inhibition can refer to* the inhibition of the expression of the enzyme by another molecule...
). Most patients (type IA) have a mutation in one of the common exons (2 to 5), and have difficulties conjugating several additional substrates (several drugs and xenobiotics). A smaller percentage of patients (type IB) have mutations limited to the bilirubin-specific A1 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
; their conjugation defect is mostly restricted to bilirubin itself.
Before the availability of phototherapy, these children died of kernicterus
Kernicterus
Kernicterus is damage to the brain centers of infants caused by increased levels of unconjugated bilirubin. This may be due to several underlying pathologic processes. Newborn babies are often polycythemic. When they break down the erythrocytes, one of the byproducts is bilirubin, which circulates...
(bilirubin encephalopathy) or survived until early adulthood with clear neurological impairment. Today, therapy includes
- exchange transfusions in the immediate neonatal period
- 12h/d phototherapy
- heme oxygenaseHeme oxygenaseThis reaction can occur in virtually every cell; the classic example is the formation of a bruise, which goes through different colors as it gradually heals: red heme to green biliverdin to yellow bilirubin...
inhibitors to reduce transient worsening of hyperbilirubinemia (although the effect decreases over time) - oral calciumCalciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
phosphate and carbonate to form complexes with bilirubin in the gut, - liver transplantationLiver transplantationLiver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
before the onset of brain damage and before phototherapy becomes ineffective at later age
Crigler-Najjar syndrome, type II
Type II differs from type I in several aspects:- Bilirubin levels are generally below 345 µmol/L (100–430; thus, there is overlap), and some cases are only detected later in life.
- Because of lower serum bilirubin, kernicterus is rare in type II.
- BileBileBile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
is pigmented, instead of pale in type I or dark as normal, and monoconjugates constitute the largest fraction of bile conjugates. - UGT1A1 is present at reduced but detectable levels (typically <10% of normal), because of single base pairBase pairIn molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
mutations. - Therefore, treatment with phenobarbitalPhenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
is effective, generally with a decrease of at least 25% in serum bilirubin. In fact, this can be used, along with these other factors, to differentiate type I and II. - The inheritance pattern of Crigler–Najjar syndrome type II has been difficult to determine but is generally considered to be autosomal recessive.
Differential diagnosis
Neonatal jaundiceNeonatal jaundice
Neonatal jaundice or Neonatal hyperbilirubinemia is a yellowing of the skin and other tissues of a newborn infant. A bilirubin level of more than 85 umol/l manifests clinical jaundice in neonates whereas in adults a level of 34 umol/l would look icteric...
may develop in the presence of sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
, hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
, hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
, hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
, hypertrophic pyloric stenosis, galactosemia
Galactosemia
Galactosemia is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Although the sugar lactose can metabolize to galactose, galactosemia is not related to and should not be confused with lactose intolerance...
, fructosemia, and so on.
Hyperbilirubinemia of the unconjugated type may be caused by
- increased production
- hemolysisHemolysisHemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
(e.g., hemolytic disease of the newbornHemolytic disease of the newbornHemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta...
, hereditary spherocytosisHereditary spherocytosisHereditary spherocytosis is a genetically-transmitted form of spherocytosis, an auto-hemolytic anemia characterized by the production of red blood cells that are sphere-shaped rather than bi-concave disk shaped , and therefore more prone to hemolysis.-Symptoms:As in non-hereditary spherocytosis,...
, sickle cell disease) - ineffective erythropoiesisErythropoiesisErythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin...
- massive tissue necrosisNecrosisNecrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
or large hematomaHematomaA hematoma, or haematoma, is a localized collection of blood outside the blood vessels, usually in liquid form within the tissue. This distinguishes it from an ecchymosis, which is the spread of blood under the skin in a thin layer, commonly called a bruise...
s)
- hemolysis
- decreased clearance
- drug-induced
- physiological neonatal jaundiceJaundiceJaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
and prematurity - liver diseases such as advanced hepatitisHepatitisHepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
or cirrhosisCirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function... - breast milk jaundiceJaundiceJaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
and Lucey-Driscoll syndromeLucey-Driscoll syndromeLucey-Driscoll syndrome is an autosomal recessive metabolic disorder affecting enzymes involved in bilirubin metabolism.It is one of several disorders classified as a transient familial neonatal unconjugated hyperbilirubinemia.-Cause:... - Crigler–Najjar syndrome and Gilbert syndrome
In Crigler–Najjar syndrome and Gilbert syndrome, routine liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
are normal, and hepatic histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
usually is, too. There is no evidence for hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
. Drug-induced case typically regress after discontinuation of the substance. Physiological neonatal jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
may peak at 85–170 µmol/L and decline to normal adult concentrations within two weeks. Prematurity results in higher levels.
Research
One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by hepatocyteHepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
transplantation.
The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since there is only one enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
working improperly, gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
for Crigler Najjar is a theoretical option which is being investigated.
See also
- Dubin-Johnson syndromeDubin-Johnson syndromeDubin–Johnson syndrome is an autosomal recessive disorder that causes an increase of conjugated bilirubin in the serum without elevation of liver enzymes . This condition is associated with a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile, and is similar to...
- Gilbert syndrome
- Rotor syndromeRotor syndromeRotor syndrome, also called Rotor type hyperbilirubinemia, is a rare, relatively benign autosomal recessive bilirubin disorder of unknown origin...
- Lucey-Driscoll syndromeLucey-Driscoll syndromeLucey-Driscoll syndrome is an autosomal recessive metabolic disorder affecting enzymes involved in bilirubin metabolism.It is one of several disorders classified as a transient familial neonatal unconjugated hyperbilirubinemia.-Cause:...
- Neonatal jaundiceNeonatal jaundiceNeonatal jaundice or Neonatal hyperbilirubinemia is a yellowing of the skin and other tissues of a newborn infant. A bilirubin level of more than 85 umol/l manifests clinical jaundice in neonates whereas in adults a level of 34 umol/l would look icteric...