Indirect Bilirubin (Unconjugated) | Direct Bilirubin (Conjugated) |
Also referred as: insoluble, prehepatic, indirect-reacting, albumin-bound bilirubin | Also referred as: posthepatic, direct-reacting, unbound bilirubin |
Normal plasmatic range: 0.2 - 0.9 mg/dL (see note below) | Normal plasmatic range: 0.1 - 0.2 mg/dL (see note below) |
Derives mainly from hemoglobin metabolism | It is the product of bilirubin metabolism within the liver |
Hydrophobic | Water soluble |
Must be conjugated in the liver before it can be excreted | Is readily excreted into bile, stool, and urine |
Most bound to albumin in plasma; a small amount free in the plasma | Only a small amount normally found within the plasma |
Never present in the urine | May be found in the urine when serum levels exceed 3-4 mg/dL (see note below) |
Can be measured only indirectly, by subtracting the direct bilirubin level from the total bilirubin level | Can be measured directly in plasma |
Current treatment for Crigler-Najjar patients is based upon phototherapy (emission range: 400-525 nm, peak emission: 450-460 nm). Patients undergo to phototherapy sessions (about 10 hours/day). Light energy is absorbed by bilirubin as it circulates in skin capillaries, resulting in conversion of insoluble bilirubin to photoisomers (referred also as photobilirubin and lumirubin) which are water-soluble and readily excreted.
Different parameters are to be considered about phototherapy:
LIGHT SOURCE:
Philips Special Blue lamps F20T12/BB or F40/BB (which are different from "regular" blue lamps labeled F20T12/B) or Philips TL 52 lamps are generally used as light source.
Factors affecting the effectiveness of phototherapy:
In the past years, technology of phototherapy devices moved from fluorescent lamps to LED as source of light.
The efficacy of LED lights in reducing total serum bilirubin levels is comparable to that of conventional light sources (fluorescent or halogen lamps).
Moreover, compared to conventional fluorescent lamps, LED have the following advantages:
HOW TO BUILD A PHOTOTHERAPY UNIT:
Another problem to face is how to build a phototherapy unit for adult patients with limited costs. Here we show how some ingenious dads have solved the problem of home phototherapy for their children
(Click on the picture to see a larger view)
Made by Gaia's dad (e-mail: info@ciami.it )
Made by Graham (e-mail: Graham)
Made by The University of Twente, The Netherlands
Ledwrap made by Philomeen Engels
LED blanket by Smart Texiles
Home phototherapy system using Royal Blue power LEDs made by Charles Murphy (e-mail: Charles Murphy)
Bililed Blue Night phototherapy unit using LEDs
Led lamp by Dutch Medical Technology
Phototherapy crib mattress from Archives of Disease in Childhood
Daytime Phototherapy Unit
How to build a sit up unit.
Some companies have developed experimental sunbeds designed for adult Crigler-Najjar patients. Among those
Other interesting sites:
Gene therapy to treat Crigler Najjar syndrome. aims to introduce a correct copy of the UGT1A1 gene into the patient's liver cells. This procedure can be accomplished by the administration of specific "vectors" which carry the genetic material to be delivered. Preclinical studies performed on the animal model of the disease (the Gunn rat) provided evidence that gene therapy may promote the correction of the disease.
Several gene therapy clinical trials are being considered as a therapeutic option for the treatment of Crigler-Najjar patients:
Title: A phase I/II, open label, escalating dose study to evaluate safety and efficacy of an intravenous injection of GNT0003 (Adeno-associated Viral Vector expressing the UGT1A1 transgene) in patients with severe Crigler-Najjar syndrome requiring phototherapy.
Abbreviated trial name: CareCN - CureCN
Purpose: To assess safety, tolerability and efficacy of a single intravenous administration of Adeno-associated Viral Vector expressing the UGT1A1 transgene in patients with severe Crigler-Najjar syndrome requiring phototherapy.
Sponsor: Genethon - Developer: Genethon and Spark Therapeutics
Sponsor:This project has received funds from the European 's Union Horizon 2020 research and innovation programme under the grant agreement number 755225 Cure CN Horizon 2020 Project
EU Clinical Trial Register number: 2017-000506-37
EU Clinical Trial Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-000506-37/NL
ClinicalTrials.gov Identifier: NCT03466463
ClinicalTrial.gov Link: https://clinicaltrials.gov/ct2/show/NCT03466463?cond=Crigler-Najjar+Syndrome&rank=1
December 2018: The first patient affected by Crigler-Najjar syndrome administered with gene therapy vector in CURE CN trial sponsored by Genethon. A second patient has been treated. No significant side effects were reported, but the reduction of hyperbilirubinemia in both treated patients was transient.
November 2020: A patient affected by Crigler-Najjar syndrome type I underwent gene therapy treatment with an higher dose of viral vector at the Papa Giovanni XXIII Hospital in Bergamo (Italy) by the Prof. Lorenzo D'Antiga's team. March 2021: A second patient has been treated on March 2021, a third on June 2021.
June 2021: Exciting results achieved so far in AAV-mediated gene therapy trial for Crigler Najjar syndrome by Prof. D'Antiga at the Congress of the European Association for the Study of the Liver. In particular, the treatment was well tolerated in the patients treated so far. The administration of the vector at the highest dose resulted in a significant reduction in unconjugated bilirubin levels, allowing the first treated patient to stop phototherapy. The study is still ongoing
Last Update March 2023: Genethon Given PRIME Status by EMA for Gene Therapy To Treat Crigler-Najjar Syndrome
August 2023: Published on New England Journal of Medicine the results of a phase 1-2 study evaluating the safety and efficacy of a single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 in patients with the Crigler-Najjar syndrome that was being treated with phototherapy.
Link to a press release from Genetic Engineering and Biotechnology News
Title: Clinical Assessment Study in Crigler-Najjar Syndrome
Abbreviated trial name: LUSTRO
ClinicalTrials.gov Identifier: NCT03078881
Purpose: Pre-Phase 1 prospective, non-interventional clinical assessment study to evaluate Crigler-Najjar syndrome subjects requiring daily phototherapy, aged 1 year and older.
Sponsor: Audentes Therapeutics (Astallas)
ClinicalTrials.gov Identifier: NCT03078881
ClinicalTrials.gov Link: https://clinicaltrials.gov/ct2/show/NCT03078881
Title: Gene Transfer Clinical Study in Crigler-Najjar Syndrome (VALENS)
Abbreviated trial name: VALENS
Purpose: Phase 1/2, multinational, open-label, ascending-dose, delayed-treatment concurrent control clinical study to evaluate the safety and preliminary efficacy of adeno-associated viral vector expressing the UGT1A1 transgene in subjects with Crigler-Najjar aged ≥1 year.
Sponsor: Audentes Therapeutics
ClinicalTrials.gov Identifier: NCT03223194
ClinicalTrials.gov Link: https://clinicaltrials.gov/ct2/show/NCT03223194
LAST UPDATE: February 2018: First patient affected by Crigler-Najjar syndrome administered with gene therapy vector in VALENS clinical trial sponsored by Audentes. Later the trial was suspended.
Crigler-Najjar syndrome has been classified into two types according to the degree of hyperbilirubinaemia and to the response to phenobarbital administration.
The more severe Crigler-Najjar type I (Online Mendelian Inheritance in Man #218800 ) is characterized by severe chronic non-haemolytic unconjugated hyperbilirubinaemia with high levels of serum bilirubin (between 20-50 mg/dL) due to the absence of bilirubin B-UDPGT (UGT1A1) activity.
In the milder Crigler-Najjar type II (known also as Arias syndrome) (Online Mendelian Inheritance in Man #606785 ), bilirubin UGT1A1 activity is only decreased and a consistently significant reduction of hyperbilirubinemia is obtained with phenobarbital treatment, which does not occur in Crigler-Najjar type I. The response to phenobarbital may represent induction on the residual UGT1A1 activity present in type II patients.
Clinically, Crigler-Najjar type I and type II syndrome are discriminated on the basis of the following clinical criteria:
Crigler Najjar type I | Crigler Najjar type II | |
Serum bilirubin concentration | 20-50 mg/dL | < 20 mg/dL |
Hepatic UGT1A1 activity | Absent | Markedly reduced |
Effect of phenobarbital on serum bilirubin concentration | None | Reduction |
Bile | Usually pale: contains small amounts of unconjugated bilirubin | Increased proportion of bilirubin monoglucoronide |
Prognosis | Kernicterus | Usually benign |
Mode of inheritance | Autosomal recessive | Most likely autosomal recessive |
Several alteration in the UGT1A1 gene have been described both in Crigler-Najjar type I and Crigler-Najjar type II patients (see The Human Gene Mutation Database). As a general rule mutations in Crigler-Najjar type I patients disrupt completely UGT1A1 activity, while mutations discovered in Crigler-Najjar type II patients have a milder effect on the protein activity even if there is considerable variability in type II, making it difficult to classify some cases.
Crigler-Najjar type I is inherited as an autosomal recessive trait. Also type II is believed to be autosomal recessive even if the pattern of inheritance is not certain. For Crigler-Najjar type II, in fact, also an autosomal dominant transmission model has been proposed.
In an autosomal recessive inheritance two copies of an altered gene located on one of the autosomes (that is, not the X or Y chromosomes) must be present for an individual to be affected with the trait or condition determined by that gene.
- An affected individual (homozygote) has two parents who are unaffected but each parent carries the altered gene (heterozygote).
- The risk of two heterozygotes, or carriers, having an affected child is 25%, 1 in 4, for each child that they have; similarly, there is a 3 in 4 chance (75%) that each child will not be affected.
- Males and females are at equal risk for being affected.
- Two affected individuals (homozygotes) usually produce children all of whom are affected as well.
Autosomal dominant inheritance is marked by the primary feature that one copy of an allele is sufficient for expression of a trait; the gene located on one of the 22 autosomes (that is, not the X or Y sex chromosome) is expressed in the heterozygous state.
- Each affected person has at least one affected parent. Exceptions may occur for one of three reasons:
Other characteristics of autosomal dominance:
- An affected person has a 50% chance of passing the trait to a child.
- Males and females are equally likely to be affected.
- Two affected people can have an unaffected child.
Related resources:
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