Crigler–Najjar syndrome is a rare inherited disorder affecting the
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
of
bilirubin
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
, a chemical formed from the breakdown of the
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consis ...
in red blood cells. The disorder results in a form of non
hemolytic
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme met ...
, which results in high levels of unconjugated bilirubin and often leads to
brain damage in infants. The disorder is inherited in an
autosomal 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 ...
manner. The annual incidence is estimated at 1 in 1,000,000.
This syndrome is divided into types I and II, with the latter sometimes called Arias syndrome. These two types, along with
Gilbert's syndrome
Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. Many people never have symptoms. Occasionally jaundice (a slight yellowish color of the skin or whites of the eyes ...
,
Dubin–Johnson syndrome
Dubin–Johnson syndrome is a rare, autosomal recessive, benign disorder that causes an isolated increase of conjugated bilirubin in the serum. Classically, the condition causes a black liver due to the deposition of a pigment similar to melanin. ...
, and
Rotor syndrome
Rotor syndrome (also known as Rotor type hyperbilirubinemia) is a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia, relatively benign, autosomal recessive bilirubin disorder characterized by non-hemolytic j ...
, make up the five known
hereditary
Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic infor ...
defects in bilirubin metabolism. Unlike Gilbert's syndrome, only a few causes of Crigler–Najjar syndrome are known.
Signs and symptoms
Signs and symptoms of Crigler-Najjar syndrome include Jaundice, diarrhea, vomiting, fever, confusion, slurred speech, difficulty swallowing, change in gait, staggering, frequent falling and seizures
Cause
It is caused by abnormalities in the gene coding for uridine diphosphoglucuronate glucuronosyltransferase (UGT1A1). UGT1A1 normally catalyzes the conjugation of bilirubin and glucuronic acid within hepatocytes. Conjugated bilirubin is more water-soluble and is excreted in bile.
Diagnosis
Type I
This is a very rare disease (estimated at 0.6–1.0 per million live births), and
consanguinity
Consanguinity ("blood relation", from Latin '' consanguinitas'') is the characteristic of having a kinship with another person (being descended from a common ancestor).
Many jurisdictions have laws prohibiting people who are related by blood fr ...
increases the risk of this condition (other rare diseases may be present).
Inheritance
Inheritance is the practice of receiving private property, titles, debts, entitlements, privileges, rights, and obligations upon the death of an individual. The rules of inheritance differ among societies and have changed over time. Offici ...
is
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 allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...
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 ...
.
Intense jaundice appears in the first days of life and persists thereafter. Type 1 is characterised by a
serum
Serum may refer to:
*Serum (blood), plasma from which the clotting proteins have been removed
**Antiserum, blood serum with specific antibodies for passive immunity
* Serous fluid, any clear bodily fluid
* Truth serum, a drug that is likely to mak ...
bilirubin usually above 345 μmol/L
0 mg/dL(range 310–755 μmol/L
8–44 mg/dL (whereas the
reference range
In medicine and health-related fields, a reference range or reference interval is the range or the interval of values that is deemed normal for a physiological measurement in healthy persons (for example, the amount of creatinine in the blood ...
for total bilirubin is 2–14 μmol/L
.1–0.8 mg/dL.
No
UDP glucuronosyltransferase 1-A1 expression can be detected in the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
tissue. Hence, there is no response to treatment with
phenobarbital
Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
, which causes
CYP450 enzyme induction. Most patients (type IA) have a mutation in one of the common
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...
(2 to 5), and have difficulties conjugating several additional substrates (several drugs and
xenobiotics
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
). A smaller percentage of patients (type IB) have
mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
limited to the bilirubin-specific A1 exon; their conjugation defect is mostly restricted to bilirubin itself.
Before the availability of
phototherapy
Light therapy, also called phototherapy or bright light therapy is intentional daily exposure to direct sunlight or similar-intensity artificial light in order to treat medical disorders, especially seasonal affective disorder (SAD) and circadi ...
, these children died of
kernicterus
Kernicterus is a bilirubin-induced brain dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is neurotoxic when its concentratio ...
(bilirubin encephalopathy) or survived until early adulthood with clear neurological impairment. Today, therapy includes
*
exchange transfusions in the immediate neonatal period
* 12 hours/day phototherapy
*
heme oxygenase
Heme oxygenase, or haem oxygenase, (HMOX, commonly abbreviated as HO) is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous ion, and carbon monoxide.
There are many heme degrading enzymes in nature. In general, on ...
inhibitors to reduce transient worsening of
hyperbilirubinemia
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
(although the effect of the drug decreases over time)
* oral
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
phosphate and carbonate to form complexes with bilirubin in the gut
*
liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person ( allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, ...
before the onset of brain damage and before phototherapy becomes ineffective at later age
Type II
The inheritance patterns of ''both'' Crigler–Najjar syndrome types I and II are
autosomal 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 ...
.
However, type II differs from type I in a number of different aspects:
* Bilirubin levels are generally below 345 μmol/L
0 mg/dL(range 100–430 μmol/L
–24 mg/dL thus, overlap may sometimes occur), and some cases are only detected later in life.
* Because of lower serum bilirubin, kernicterus is rare in type II.
*
Bile
Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver b ...
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 pair mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
.
* Therefore, treatment with
phenobarbital
Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
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.
Differential diagnosis
Neonatal jaundice
Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral pals ...
may develop in the presence of
sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is foll ...
,
hypoxia,
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 be ...
,
hypothyroidism
Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as ...
,
hypertrophic pyloric stenosis
Pyloric stenosis is a narrowing of the opening from the stomach to the first part of the small intestine (the pylorus). Symptoms include projectile vomiting without the presence of bile. This most often occurs after the baby is fed. The typical a ...
,
galactosemia
Galactosemia (British galactosaemia, from Greek γαλακτόζη + αίμα, meaning galactose + blood, accumulation of galactose in blood) is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galacto ...
,
fructosemia, etc.
Hyperbilirubinemia of the unconjugated type may be caused by:
* increased production
**
hemolysis
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
(e.g.,
hemolytic disease of the newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the fiv ...
,
hereditary spherocytosis
Hereditary spherocytosis (HS) is a congenital hemolytic disorder, wherein a genetic mutation coding for a structural membrane protein phenotype leads to a spherical shaping of erythrocytic cellular morphology. As erythrocytes are sphere-shaped ( ...
,
sickle cell disease
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red b ...
)
** ineffective
erythropoiesis
Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell.
It is stimulated by decre ...
** massive tissue
necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dig ...
or large
hematoma
A hematoma, also spelled haematoma, or blood suffusion is a localized bleeding outside of blood vessels, due to either disease or trauma including injury or surgery and may involve blood continuing to seep from broken capillaries. A hematoma is ...
s
* decreased clearance
**
drug-induced
** physiological neonatal
jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme met ...
and
prematurity
**
liver diseases such as advanced
hepatitis
Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...
or
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
** breast milk
jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme met ...
and
Lucey–Driscoll syndrome
** Crigler–Najjar syndrome and
Gilbert syndrome
In Crigler–Najjar syndrome and Gilbert syndrome, routine
liver function tests
Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin t ...
are normal, and
hepatic
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
histology
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vi ...
usually is normal, too. No evidence for
hemolysis
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
is seen. Drug-induced cases 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.
Treatment
Plasmapheresis and phototherapy are used for treatment. Liver transplant is curative.
Research
A San Francisco-based company named Audentes Therapeutics is currently investigating the treatment of Crigler–Najjar syndrome with one of their gene replacement therapy products, AT342. Preliminary success has been found in early stages of a phase 1/2 clinical trial.
One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by
liver cell
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein biosynthesis, Protein synthesis
* Storage protein, Protein storage
* Transformation of carboh ...
transplantation.
The homozygous
Gunn rat Dr. Charles Kenneth Gunn discovered a mutant rat in 1934 at the Connaught Laboratory in Toronto, Canada. These rats were jaundiced and the defect (a lack of the enzyme uridine diphosphate glucuronyltransferase) was transmitted as an autosomal reces ...
, which lacks the enzyme
uridine diphosphate glucuronyltransferase
Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...
(UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since only one
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
is working improperly,
gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human D ...
for Crigler-Najjar is a theoretical option which is being investigated.
Eponym
The condition is named for
John Fielding Crigler
John Fielding Crigler (11 September 1919 - 13 May 2018) was an American pediatrician. Along with Victor Assad Najjar, Crigler is known for Crigler–Najjar syndrome. He studied medicine at the Duke University School of Medicine, graduating in 1943 ...
(1919 – May 13, 2018), an American pediatrician and
Victor Assad Najjar (1914–2002), a Lebanese-American pediatrician.
References
External links
*
*
{{DEFAULTSORT:Crigler-Najjar Syndrome
Syndromes affecting the hepatobiliary system
Heme metabolism disorders
Hepatology
Rare syndromes