Unconjugated Hyperbilirubinemia Treatment & Management

Updated: May 02, 2016
  • Author: Hisham Nazer, MB, BCh, FRCP, , DTM&H; Chief Editor: BS Anand, MD  more...
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Treatment

Approach Considerations

Gilbert syndrome

Once the diagnosis of Gilbert syndrome is established, the most important aspect of treatment is reassurance. The clinician must make it perfectly clear to the patient that the syndrome is essentially benign, is not associated with increased morbidity (except for an increased incidence of side effects from certain drugs, such as the antitumor agent irinotecan), has an excellent prognosis, and is associated with normal life expectancy. In light of the benign and inconsequential nature of Gilbert syndrome, the use of medications to treat patients with this condition is unjustified in clinical practice.

Crigler-Najjar syndrome

Patients with Crigler-Najjar syndrome type 2 may not require any treatment or can be managed with phenobarbital. By contrast, prompt treatment of kernicterus is required in patients with Crigler-Najjar syndrome type 1 to avoid the potentially devastating neurologic sequelae.

Emergent management of bilirubin encephalopathy involves plasma exchange transfusion, which acts by removing the bilirubin-saturated albumin and providing free protein, which draws bilirubin from the tissues.

Plasma exchange should be accompanied by long-term phototherapy, which helps in the conversion of bilirubin to more soluble isoforms that can be excreted in the urine. Oral calcium phosphate may be a useful adjuvant to phototherapy in Crigler-Najjar syndrome type 1. (It should be kept in mind, however, that phototherapy restricts the life of the child and his or her family. Phototherapy also causes insensible water loss, diarrhea, tanning of the skin, and problems in maintaining body temperature.)

Inhibitors of heme oxygenase, such as tin protoporphyrin or tin-mesoporphyrin, may be helpful in reducing bilirubin levels emergently, but the effect is short-lived.

Therapies based on gene and cell transfer techniques, although largely experimental at the present time, are likely to play an important role in the management of Crigler-Najjar syndrome in the future. [61, 62]

Rescue phototherapy and phototherapy in transport for severe unconjugated hyperbilirubinemia

High-intensity light-emitting diode (LED) beds may be a safe rescue therapy for severe unconjugated neonatal hyperbilirubinemia. [63]  In a study of 200 jaundiced neonates at or over 35 weeks' gestation who were phototherapy candidates, use of a super LED bed achieved significantly higher success rates of intensive phototherapy (87%) compared with conventional intensive phototherapy with triple fluorescent tube units (64%). There was also a significantly greater reduction in bilirubin levels for both hemolytic and nonhemolytic subgroups in the super LED bed treatment group than in similar subgroups in those received standard intensive phototherapy. [63]  

In a retrospective study over an 11-year period of 147 neonates with severe unconjugated hyperbilirubinemia at risk of requiring exchange transfusion who were being transported for treatment, those who received phototherapy during transport  (n = 104) were less likely to require exchange transfusion (19.2%) than neonates who did not receive phototherapy during transport (n = 43). [64] Moreover, although it did not reach statistical significance, the group that received phototherapy during transport also had an increased reduction in serum bilirubin levels from before to after transport compared to the group that did not receive phototherapy during transport.

Prevention

Use drugs that displace bilirubin, such as sulfa, salicylates, furosemide, ampicillin, and ceftriaxone, with caution (or completely avoid).

The bilirubin level may rapidly rise to dangerous levels under certain conditions, such as fasting, infections, trauma, fever, and poor compliance with therapy.

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Nonsurgical Correction of Bilirubin Levels

Crigler-Najjar syndrome type 1

Therapeutic response varies according to the type of Crigler-Najjar syndrome being treated. Crigler-Najjar syndrome type 1 does not respond to phenobarbital therapy, and patients may require repeated exchange transfusions followed by long-term phototherapy to prevent neurologic complications.

Other therapies include plasmapheresis, hemoperfusion, and the administration of cholestyramine, calcium phosphate, oral agar, and orlistat. [3] An approach to therapy using Sn-protoporphyrin, a heme oxygenase inhibitor, was introduced to prevent an increase in serum bilirubin levels. [4] In patients with Crigler-Najjar syndrome type 1, however, liver transplantation remains the only guaranteed form of therapy. This surgery should occur prior to the onset of kernicterus.

Phototherapy

Phototherapy causes the formation of water-soluble bilirubin isomers that can be secreted in bile without conjugation.

Patients with Crigler-Najjar syndrome type 1 generally need 10-16 hours of treatment per day. Monitor the intensity of light to keep it at a level of at least 4-10 µW/cm2/nm. The appropriate wave length is in the blue-green spectrum at 425-475 nm.

The efficacy of phototherapy is dose dependent; therefore, the response to phototherapy increases when the dose is increased. Efficacy of phototherapy can be increased by increasing the intensity of light, by increasing exposure of body surface, and by using reflecting surfaces (eg, mirrors). Double-surface phototherapy has also been used in some cases to improve the outcome. Oral calcium phosphate may be a useful adjuvant to phototherapy in Crigler-Najjar syndrome type 1.

The effectiveness of phototherapy decreases after age 3-4 years, because the ratio of skin surface area to body mass is reduced. [65]

Problems associated with phototherapy include restriction of activity and play, poor compliance, inability of the patient to travel or take vacations, irritation from the eye shades, difficulties in temperature maintenance, tanning of the skin, embarrassment from the need to be nearly nude during phototherapy, and difficulty in procuring phototherapy lamps. Long-term phototherapy may lead to developmental delay, impaired weight gain, and possible psychological disturbances.

More recent studies indicate that conventional and intensive phototherapy is also associated with DNA damage in term infants with hyperbilirubinemia. [66]

Newer methods of delivering phototherapy, such as sit-up phototherapy units, may reduce phototherapy time by 50% while maintaining effectiveness and, thus, may allow a child to attend school.

Exchange transfusion

As previously mentioned, emergent management of bilirubin encephalopathy involves plasma exchange transfusion, which acts by removing bilirubin-saturated albumin and providing free protein, which draws bilirubin from the tissues. Plasma exchange should be accompanied by long-term phototherapy. Treatment with exchange transfusions and phototherapy should be intensified early.

Gene therapy

Gene therapy offers the greatest potential for cure for patients with Crigler-Najjar syndrome. Successful cloning of the gene responsible for bilirubin glucuronosyltransferase activity offers the hope of future gene therapy to correct this deficiency. [61]

Clinically significant improvement can be achieved even with partial enzyme replacement. About 5% of normal UGT 1A1 can significantly lower the plasma bilirubin concentration and decrease the need for phototherapy.

Long-term monitoring

Despite medical treatment, patients are at risk for sudden rises in serum bilirubin levels. Parents and physicians should be alert to such bilirubin crises. The child usually presents with altered sensorium, incoordination, slurring of speech, and weakness. Coma may eventually occur.

Treatment of severe episodes of hyperbilirubinemia includes intense phototherapy, exchange transfusion, plasmapheresis, and tin-mesoporphyrin. During periods of illness, kernicterus may occur at a low level of bilirubin.

Crigler-Najjar syndrome type 2

Phenobarbital therapy has been shown to be effective in reducing plasma bilirubin levels in patients with Crigler-Najjar syndrome type 2. Administration of 60-180 mg/day of the drug (in divided doses) can reduce serum bilirubin levels by at least 25%. A response should be expected within 2-3 weeks. A similar benefit can be observed with clofibrate, which is associated with fewer adverse effects. (Clofibrate is no longer on the US market.) However, patients with the type 2 syndrome often do well even without therapy.

In rare cases, however, patients with Crigler-Najjar syndrome type 2 require exchange transfusions or long-term phototherapy.

Gilbert syndrome

No therapy is necessary for patients with Gilbert syndrome. However, many therapeutic approaches have been used. As with Crigler-Najjar type II syndrome, phenobarbital has been shown to decrease bilirubin production. The most important aspect in the care of patients with Gilbert syndrome, however, is recognition of the disorder and its inconsequential nature.

Toxicity

Irinotecan toxicity in Gilbert syndrome is of some concern, however. As a result of a mutation in the UGT1A1 gene promoter, affected patients show reduced inactivation of the active topoisomerase inhibitor 7-ethyl-10-hydroxycampothecin (SN-38). Glucuronidation rates of the active metabolite SN-38 are significantly lower in people who are homozygous and heterozygous for the TA-TATAA variant allele than in those with the wild-type genotype (TATAA).

In patients with Gilbert or Crigler-Najjar syndrome, reduced glucuronidation of SN-38 leads to SN-38 toxicity and causes symptoms such as diarrhea. Preliminary results from clinical trials suggest that screening cancer patients for the UGT1A1 promoter polymorphism may reduce the prevalence of irinotecan toxicity. Until this evidence is available, caution is warranted before irinotecan is prescribed to this subset of patients.

Pharmacogenetics

The clinical relevance of pharmacogenetics in Gilbert syndrome has yet to be determined. Although impaired glucuronidation and excretion of certain drugs have been reported, such impairment has not resulted in any adverse clinical events, and the risk probably remains more theoretical than real. [54, 55]

Neonatal jaundice

No treatment is needed for physiologic jaundice. For breast milk jaundice and other types of nonphysiologic jaundice, phototherapy can be used.

Phototherapy, which consists of exposing the infant's skin to light, is a safe and efficient method to reduce the toxicity of bilirubin and to increase its elimination. The use of phototherapy decreases the risk that the total serum bilirubin concentration will reach the level at which exchange transfusion is recommended. [67]

Maintaining adequate hydration and urine output is important during phototherapy to prevent dehydration.

An uncommon complication of phototherapy is the so-called bronze baby syndrome. This occurs in some infants with cholestatic jaundice and is manifested by a dark, grayish brown discoloration of the skin, serum, and urine. The condition gradually resolves without sequelae within several weeks after discontinuation of therapy.

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Liver and Hepatocyte Transplantation

Liver transplantation

Liver transplantation remains the sole definitive treatment for Crigler-Najjar syndrome type 1. [68, 69] Cadaveric orthotopic and auxiliary and living related liver transplantation have resulted in excellent survival rates and prognoses.

Early liver transplantation in patients with Crigler-Najjar syndrome type 1 decreases the incidence of neurologic deficits, especially for patients in whom reliable administration of phototherapy cannot be guaranteed. [70, 71]

Hepatocyte transplantation

Hepatocyte transplantation has become an effective therapy for patients with inborn metabolic errors. It involves catheterization of the portal vein and an infusion of donor hepatocytes. [70, 72, 73, 74]

The immunosuppression regimen is similar to that administered to patients receiving whole-organ transplantation and currently includes tacrolimus and prednisolone.

Stem cells and stem cell–derived hepatocytes should offer the potential to overcome current limitations on the supply of hepatocytes and on the extent of repopulation of the liver after transplantation. [75]

Hepatocyte transplantation has been reported to decrease the need for phototherapy and to increase the activity of UGT to 5.5% of normal.

In a report, hepatocyte transplantation resulted in bilirubin levels decreasing to and maintaining long-term stabilization at about 50% of the values found prior to cell infusion. [76]

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