This is a web site devoted to children and adults with the Crigler-Najjar syndrome and their
families. It has been created with support and funding from The Rockefeller University.
Our mission is to provide information about the Crigler-Najjar syndrome to persons with
the disorder, their families and the health professionals who take care of these children.
We plan to keep this information updated as new research is published.
We expect to improve this web site considerably based on your feedback. Please contact
us with ideas and suggestions for improvement. If there is information or material you
would like to see included in this site, please send it to us by mail or email.
We will take great care to ensure that all the information on this web site is accurate.
However, before using this information for patient care, you should also confirm from other
sources that it is current, accurate and relevant. Please note that the material on this web
site is for information only and is not intended to provide specific medical advice to
patients. We cannot be held responsible for any inaccuracies in the information on this
web site or for differences of opinion between authorities.
Jerold F. Lucey, MD
Harry Wallace Professor of Neonatology
Department of Pediatrics
University of Vermont College of Medicine
Burlington, Vermont 05405
Gautham Suresh, MD
Burlington, Vermont 05405
This site is sponsored by the Rockefeller University
Site created on 08/04/99 and updated on Mon, Sep 9, 2002
Note: This site is no longer available:
these pages have been rescued from the
In order to understand the Crigler-Najjar syndrome well, it is essential to first understand
what bilirubin is and how bilirubin is processed in the human body. This section will help
you understand what jaundice is, why children with Crigler-Najjar syndrome have jaundice
and how the different methods of treatment of this condition work.
What is jaundice?
Jaundice is a yellow discoloration of the skin and the whites of the eyes as a result of
having a high bilirubin level in the blood.
What is bilirubin?
Bilirubin (Latin, bilis, bile; ruber, red) is a red bile pigment formed by the breakdown of
hemoglobin, which is the red oxygen-carrying substance present in red blood cells
circulating in blood. There are also other sources of bilirubin, like myoglobin, a protein
present in muscle and enzymes such as cytochromes. Hemoglobin itself consists of two
parts, heme and globin. An enzyme called heme oxygenase acts on heme to produce
biliverdin, which in turn is converted into bilirubin.
What happens to bilirubin after it is formed?
Bilirubin's ultimate destination is bile, which is made by the liver, but there are several
steps it has to go through before it can enter bile. Bilirubin does not dissolve easily in water
and therefore it needs a carrier to be transported in the blood. This carrier is albumin.
Bilirubin 'sticks' to the albumin in the blood and is carried to the liver. When it reaches the
liver cells, bilirubin lets go of albumin and is taken up into the liver cells. Inside the liver
cells bilirubin is combined with a substance called glucuronic acid and is changed into
conjugated bilirubin. Prior to this it is called unconjugated bilirubin.
Conjugation is a very important step because it makes the bilirubin water soluble, enabling
it to get into the bile and be excreted. A crucial enzyme is responsible for the conjugation
of bilirubin and this enzyme is called UDP glucuronosyl transferase (or UGT). Bile (with the
conjugated bilirubin in it, along with many other substances) flows out from the liver into
the bile duct, the gall bladder and finally enters the intestine. Bile has a golden yellow-
green color because of the bilirubin in it.
In the intestine, the conjugated bilirubin can follow two paths. It can be excreted in the
stool after being changed into urobilinoids. Alternatively, the process of conjugation can
get reversed by an enzyme called beta glucuronidase, which converts the conjugated
bilirubin back into unconjugated bilirubin. Unlike conjugated bilirubin, unconjugated
bilirubin can get reabsorbed from the intestine back into the blood. This process is called
In persons with Crigler-Najjar syndrome, the crucial enzyme UGT is either missing or is
decreased in quantity or activity. Because of this, unconjugated bilirubin cannot get
conjugated or is conjugated in small quantities. Therefore it cannot be excreted into the
bile and remains in the blood, causing jaundice. If the enzyme is totally missing the person
has a severe disorder, called Crigler-Najjar syndrome type I. If the enzyme is decreased in
amount or activity, then the disorder is milder and it is called Crigler-Najjar syndrome type
II (also known as Arias syndrome). Thus the Crigler-Najjar syndromes are best thought of
as deficiencies of the enzyme UDP glucuronosyl transferase. the mildest form of
decreased enzyme activity is known as Gilbert Syndrome.
The dangers of high bilirubin levels in the blood have best been studied in newborn
babies, who, in the first week of life often have jaundice. In most babies the jaundice is
mild and goes away in a few days without any complications. However, there are several
conditions that can cause dangerously high levels of jaundice in newborn babies, leading
to a form of brain damage called kernicterus. Many of these conditions result from an
excessive breakdown of red blood cells (called hemolysis), thereby resulting in the
formation of excess amounts of bilirubin, much more than the body can handle.
When there is a dangerously high level of bilirubin in the blood, it can cross into the brain
and cause damage to certain parts of the brain, damage which can lead to permanent
disabilities and even death.
The Crigler-Najjar syndrome is an inherited disorder of bilirubin metabolism caused by a
deficiency or absence of the enzyme bilirubin uridinediphosphoglucuronate glucuronosyl
transferase (UGT). There are two types of Crigler-Najjar syndrome. In type I there is no
detectable activity of the hepatic enzyme UGT. This results in a severe form of the
disease. In type II, also known as Arias syndrome, levels of UGT are <10% of normal.
Since some enzyme activity is present, the jaundice is less severe. The following sections
describe the etiology, clinical features, diagnosis, management and prognosis of Crigler-
Najjar syndrome type I. The articles listed in the bibliography provide more detailed
descriptions of the material here.
Crigler-Najjar syndrome type I is an autosomal recessive disorder. Bilirubin is conjugated
with glucuronic acid by the enzyme bilirubin uridine diphosphate glucuronosyl transferase
(B-UGT). UGTs are a group of enzymes that mediate conjugation of many substances with
glucuronic acid. They are located on the endoplasmic reticulum and on the nuclear
envelope. There are many isoforms, which differ in amino acid sequence, and have
different but partially overlapping substrate specificity. They are divided into two major
groups, UGT1 and UGT 2, based on the extent of structural homology of cDNAs. UGT1
contains the two isoforms which conjugate bilirubin. UGT2 contains isoforms which
conjugate steroids and other substances. The synthesis of these enzymes is controlled by
a large gene complex (at least 110 kb) on chromosome 2. This complex consists of four
consecutive exons (exons 2 - 5) at the 3' end that encode the identical carboxy-terminal
regions of all UGT isoforms expressed from this locus. . Mutations of these exons cause
deficiencies of all UGT1 isoforms. Upstream to the common region exons, at the 5' end, is
a series of at least seven exons (1A - 1G), each encoding the variable amino-terminal
regions of bilirubin UGT1 and UGT2 respectively. Exon 1A encodes the amino-terminal
domain of human bilirubin-UGT1, while 1D encodes bilirubin-UGT2. Exons 1F and 1G
encode the two phenol UGTs. Because bilirubin UGT1 is the only physiologically
significant isoform in bilirubin glucuronidation, mutations in any of its five exons can cause
CN type 1 or 2, depending on the severity of its impact on enzyme activity. All patients with
CN syndromes have been found to have mutations or deletions in exon 1A, 2, 3, 4 or 5,
five exons that encode bilirubin UGT1. The exact nature and extent of the mutations and
deletions are variable, with the number of mutations described (currently more than 20)
steadily increasing over the years.
The main clinical problem is jaundice. Typically it starts in the first few days of life and
instead of subsiding like physiologic or breast milk jaundice does, persists and increases
over the next few days to weeks. There are no other signs or laboratory findings of
jaundice from other pathologic causes such as hemolysis or sepsis. In the early stages it
may be difficult to differentiate Crigler-Najjar syndrome from jaundice associated with
breast-feeding. The jaundice is almost entirely from unconjugated jaundice and there is no
elevation of conjugated bilirubin.
The level of jaundice can rise rapidly to high and dangerous levels under certain situations.
Such exacerbations ('bilirubin crisis') can occur from hemolysis, infections, fever, trauma
(including crush injuries, which can release large amounts of myoglobin), vaccination,
fasting, surgery and open liver biopsy. If for some reason treatment is stopped (non-
during travel and during adolescence, when teenagers have become non-compliant with
The constant presence of jaundice can be a significant cosmetic problem to these children
and can impair their social interactions with peers, especially during adolescence. They
are sometimes mistakenly thought to have hepatitis.
The possibility of Crigler-Najjar syndrome should be considered when there is a marked
elevation of unconjugated bilirubin in the newborn period or infancy without any other
evident cause. Thus, evidence of hemolysis, extravascular collections of blood, sepsis,
hypothyroidism are all absent. Without treatment, the jaundice shows a continually rising
50 mg/dL, with virtually all the pigment being unconjugated bilirubin. The hemoglobin
levels, reticulocyte counts, bone marrow morphology and red blood cell survival are all
normal. Liver function studies are normal and there are no abnormalities of the
extrahepatic biliary system. No bilirubin is found in the urine. Feces are of normal color,
despite low levels of fecal urobilinogen. The bile is colorless or pale yellow and contains
little or no bilirubin. Of the small amount of bilirubin present in bile, the majority is
unconjugated with small amounts of monoconjugates and traces of diconjugates. A liver
biopsy shows normal hepatic morphology under the light microscope (except for scattered
bile plugs in a few canaliculi) and, on electron microscopy, a non-specific prominence of
the smooth endoplasmic reticulum. Definitive diagnosis of Crigler-Najjar syndrome type I
requires an assay of the enzyme UGT in hepatic tissue obtained by biopsy. The activity of
this enzyme is undetectable. The viability of the sample should be tested before declaring
The mainstay of treatment for patients with Crigler-Najjar syndrome type I is phototherapy.
Phototherapy has been successful in controlling bilirubin levels for years in most of these
patients. These children generally need anywhere from 10 to 16 hours of phototherapy a
day. This is generally delivered when the child is asleep and most patients with this
disorder have specially designed phototherapy beds. Care must be taken to cover the
eyes during phototherapy. The intensity of light delivered by the phototherapy unit must be
carefully monitored with a radiometer and maintained at a level of at least 4 to 10
microwatts/square cm/nanometer. Higher intensities, for example, up to 40 or 50
microwatts/square cm/nanometer are more effective. If light intensity is decreased, the
bulbs have to be changed. Light sources that deliver the appropriate wavelengths of light
(425 - 475 nanometers) must be used. The most effective wavelengths are in the blue-
greeen spectrum. 'Special blue' fluoroscent tubes are an effective source of light in the
blue spectrum. They are labeled F20T12/BB or TL52/20W (Philips) and are different from
regular blue tubes (labeled F20T12/B). The greater the surface area of the body that is
exposed to light and the greater the intensity of light falling on the skin, the greater is the
efficacy of phototherapy. Therefore double surface phototherapy is much more effective
than single surface phototherapy. Such double surface phototherapy can be delivered by
phototherapy units which deliver light from above the patient as well as from below,
generally through transparent material upon which the patient lies. Placing reflecting
increases the efficacy of the phototherapy. A commercially made phototherapy bed for
Crigler-Najjar syndrome type I has recently become available.
Unfortunately such prolonged phototherapy severely restricts the child's lifestyle. Traveling
and vacations can be problematic (a portable form of the phototherapy bed has been
designed). Phototherapy becomes less effective with age and children can become non-
compliant with treatment. Side effects of phototherapy include increased insensible water
loss, diarrhea and tanning of the skin. The requirement to be almost nude during
phototherapy can cause embarrassment to some children and can cause problems with
maintenance of body temperature. The protective pads used for the eyes can irritate the
eyes. The availability and the cost of lamps has been a problem for some families.
Measures to decrease entero-hepatic circulation
Oral calcium phosphate can potentially be an useful addition to therapy in Crigler-Najjar
syndrome type I. A modest effect was found in a placebo-controlled double-blind study
which included five patients with Crigler-Najjar syndrome type I. Administered as a mixture
of calcium carbonate and calcium phosphate, it caused a decrease in mean bilirubin levels
of around 18%. There are anecdotal reports of patients have also been treated with
cholestyramine and agar but the efficacy of these therapies has not been well studied.
Other therapies tried
Ursodeoxycholic acid, bilirubin oxidase, antioxidants, calcium infusions, clofibrate,
flumecinol, chlorpromazine and urine alkalinization have all been reported as potential
therapies in Crigler-Najjar syndrome type I. The exact role of these agents in therapy
remains to be defined. Phenobarbitone therapy may be tried early in the clinical course
when it is uncertain if the patient has Crigler-Najjar syndrome type I or type II but it is
ineffective in the treatment of type I disease.
Avoidance of drugs that displace bilirubin
The following drugs can displace bilirubin from albumin, they should be used with caution
or not at all, especially when the bilirubin level is high: sulfisoxazole, sulfadiazine, other
sulfa drugs, indomethacin, salicylates, furosemide, ampicillin, ceftriaxone, intravenous lipid
emulsions. Also, free fatty acids, which can be elevated in sepsis and hypoxia can
The rate limiting step in the catabolism of heme to bile pigments is catalyzed by the
enzyme heme oxygenase. Tin mesoporphyrin and tin protoporphyrin are synthetic
analogues of heme which competitively inhibit heme oxygenase, thereby decreasing the
production of bilirubin and lowering plasma bilirubin levels. The unmetabolized heme is
excreted into bile. Tin-mesoporphyrin is currently the agent of choice for clinical use
because its in vivo potency in inhibition of heme oxygenase activity in animals is
substantially greater, and because of its stability and photophysical properties. It is
administered by intramuscular injection. Several randomized trials of the efficacy and
safety of tin-mesoporphyrin in preventing or treating hyperbilirubinemia have been
conducted in full term and preterm newborn infants. These trials show that tin-
mesoporphyrin reduces plasma bilirubin levels and either reduces or eliminates the need
for phototherapy with minimal side-effects.
Tin mesoporphyrin has been used in two 17year old boys with Crigler-Najjar syndrome
type I who had recent neurological deterioration with high bilirubin levels. They were
consumed constant weight-maintaining diets. They were treated with intermittent
plasmapheresis and two periods of tin-mesoporphyrin therapy comprising, in the first study
period, 40 doses of 0.5 micromoles/kg and in the second study period, 70 doses of 1
micromoles/kg. Plasma bilirubin levels were decreased in both patients to varying degrees
as was the rebound hyperbilirubinemia which occurs after plasmapheresis. The treatments
were well tolerated and no progression of the pre-existing neurological impairments
occurred during the clinical trials. Both patients experienced episodic mild reversible
cutaneous photosensitivity manifested by slight erythema of sun-exposed areas. It was
noted that after around 8 to 10 weeks of therapy with tin-mesoporphyrin both patients
displayed an 'escape' of the bilirubin effect from the effects of the drug, the mechanism of
which is uncertain. These two patients also developed mild iron-deficiency anemia, which
responded to iron supplementation.
Tin mesoporphyrin has been used in a 21 month old infant with Crigler-Najjar syndrome
type I, again reducing bilirubin levels and reducing the need for phototherapy. Tin-
mesoporphyrin has also been used in the management of a 22 year old with Crigler-Najjar
syndrome type I who developed a bilirubin crisis following non-compliance with
phototherapy. Tin-mesoporphyrin can be an useful pharmacologic adjunct to phototherapy
and other treatments to control episodes of acute severe jaundice in Crigler-Najjar
syndrome type I.
Several patients with CN syndrome type 1 have undergone liver transplantation, which is
an effective way to provide the missing enzyme UGT1. Successful transplantation has
resulted in very low or normal bilirubin levels and has eliminated the need for
phototherapy. However these benefits have to be weighed against the risks and
complications of liver transplantation, which is a major surgical procedure. Possible
complications of liver transplantation include rejection of the transplanted organ, bleeding,
hepatic artery thrombosis, bile duct leaks, and infection. Transplanted patients receive
long term immunosuppressant therapy and require periodic blood testing, periodic
physician visits and hospitalization for procedures and complications. Two types of liver
transplantation have been performed, orthotopic liver transplantation and auxiliary liver
transplantation. In orthotopic liver transplantation the patients liver is removed and a new
donor liver is inserted in its place. In auxiliary liver transplantation only part of the patient's
liver, usually the left lateral segment, is replaced with a size-matched donor graft. In this
procedure, because a portion of the patient's own liver is left in place, the transplanted
liver can be surgically removed if there is rejection, allowing the native liver to function as
usual, and returning the patient to the pretransplant state with regard to
immunosuppression and phototherapy. Also, if other definitive therapy becomes
established for Crigler-Najjar syndrome in the future, such as gene therapy, the definitive
therapy can be applied to the native liver, allowing the donor liver to be removed and
immunosuppression to be stopped. Therefore, it can be treated as a temporizing measure
until definitive treatment is discovered. Though auxiliary transplantation has advantages
over orthotopic liver transplantation, it is technically more difficult to perform.
One patient, a 10 year old girl with Crigler-Najjar syndrome type 1 has been treated with
hepatocyte transplantation. In this procedure the patient’s portal vein was catheterized
percutaneously and donor hepatocytes were infused over a period of 15 hours with
invasive hemodynamic monitoring. She was treated with steroids before and after the
procedure and with phenobarbitone after the procedure. After the procedure the patient's
of normal and eleven months after the procedure her bilirubin level was 14 mg/dL.
However she still required 6 to 7 hours of phototherapy every day, which was less than the
10 - 12 hours per day that she had been receiving before the procedure. The long-term
results of this procedure are awaited (see www.unmc.edu/news/nejom.htm).