Welcome to the Crigler-Najjar Syndrome Web Site

Welcome to the Crigler-Najjar Syndrome Web Site

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

Assistant Professor

Department of Pediatrics

University of Vermont College of Medicine

Burlington, Vermont 05405

Contact Information

www.crigler-najjar.com

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

“Wayback machine”

http://www.archive.org/web/web.php

BILIRUBIN BASICS

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

entero-hepatic circulation.

Why do persons with Crigler-Najjar syndrome have jaundice?

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 having a high bilirubin level

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.

Types of Crigler-Najjar Syndrome

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 1

Genetics and Molecular Biology

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.

Clinical Features

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-

compliance) the bilirubin can rise rapidly to dangerous levels. Typically this has happened

during travel and during adolescence, when teenagers have become non-compliant with

therapy.

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.

Diagnosis

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

trend.

Laboratory studies show total plasma bilirubin levels ranging from 15 mg/dL to more than

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

this result.

Management

Phototherapy

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

surfaces such as mirrors around the child, in order to reflect light onto the skin also

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

displace bilirubin.

Tin mesoporphyrin

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

hospitalized for more than 400 days, underwent 10 hours of phototherapy nightly and

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.

Liver tranplantation

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.

Hepatocyte transplantation

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

bile showed 33% bilirubin glucuronides (mostly diglucuronide), the UGT activity was 5.5%

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).