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Patient information: Gilbert's syndrome
Namita Roy Chowdhury, PhD
Jayanta Roy Chowdhury, MD, MRCP
UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.1 is current through December 2006; this topic was last changed on October 16, 2006. The next version of UpToDate (15.2) will be released in June 2007.
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DEFINITION — Gilbert's syndrome is an inherited disorder of the liver that results in an overabundance of a substance known as bilirubin. Other names for this mainly unharmful disorder are constitutional hepatic dysfunction and familial nonhemolytic jaundice.
CAUSES — Bilirubin is normally present in the blood in small amounts. It is a by-product of the breakdown of hemoglobin in old red blood cells, and it is usually converted by the liver into a form that can be excreted from the body in stool. This process of transformation and excretion comprises a number of steps. Abnormalities at any of these steps can cause blood levels of bilirubin to rise above normal.
People with Gilbert's syndrome have an inherited abnormality that causes reduced production of an enzyme involved in processing bilirubin. As a result, a form of bilirubin (known as unconjugated bilirubin) accumulates in the blood, sometimes causing yellowing of the skin or eyes.
Every affected person has two copies of the abnormal gene responsible for Gilbert's syndrome. Because over half of the people in the general population have at least one abnormal copy of the gene, inheriting two abnormal copies (one from the mother and one from the father) is not uncommon. Interestingly, people who have only one copy may have slightly higher levels of unconjugated bilirubin, but do not have Gilbert's syndrome.
In some studies, more than 50 percent people had at least one copy of the abnormal gene while almost one in ten had two copies. However, for reasons that are not entirely understood, not all people who have two copies of the abnormal gene develop Gilbert's syndrome .
SYMPTOMS — Most patients with Gilbert's syndrome have no symptoms. The disorder is frequently diagnosed by coincidence when a lab test done for another reason (such as a life insurance examination) shows an abnormally high amount of unconjugated bilirubin.
When the level of unconjugated bilirubin rises beyond a certain point, the bilirubin pigment begins to discolor the whites of the eyes (making them appear light yellow). With even higher levels, the skin may also become yellow (jaundice). This potentially alarming appearance makes many people with Gilbert's syndrome see their healthcare provider.
Levels of bilirubin can fluctuate in people with Gilbert's syndrome. They may be highest after an infection (such as the flu), following periods of fasting, and after menstrual periods in some women.
Gilbert's syndrome may also become apparent when an affected person takes certain drugs that require the enzyme involved in bilirubin processing in the liver. A cancer drug called irinotecan is an example.
Because males tend to produce higher levels of bilirubin, the disorder is more likely to be detected in men. Similarly, it is rarely diagnosed before puberty because production of bilirubin increases at this point.
DIAGNOSIS — The diagnosis of Gilbert's syndrome is suspected in people who have persistent, slightly elevated levels of unconjugated form of bilirubin without any other apparent cause. Thus, a clinician may order several blood tests and possibly and ultrasound of the liver to make sure that there is no other cause of the high bilirubin.
A test that is commonly performed is referred to as "caloric deprivation". Patients are asked to consume fewer than 400 calories over a 24 hour period. The bilirubin level is measured before and after the period of calorie restriction. In patients with Gilbert's syndrome, the level increases significantly. Combined with the other tests done to exclude liver and blood disorders, this test is sufficient to diagnose Gilbert's syndome.
Genetic testing can also confirm the diagnosis; however, genetic testing is not widely available and is generally not required unless there is uncertainty despite other tests. The University of Chicago Genetics Laboratory (telephone 1-888-UC-GENES, web address
www.genes.uchicago.edu) offers such testing.
TREATMENT — No specific therapy is required for patients with Gilbert's syndrome. A clinician's most important role in the management of this disorder is to warn patients of the increase in side effects from certain drugs, and that they should expect that the eyes or skin may become mildly yellowed especially after periods of illness or fasting.
It may be wise to check with a healthcare provider before taking any new medications. Care should be taken not to consume more than the recommended amount of acetaminophen (Tylenol®) since people with Gilbert's syndrome may be at greater risk for liver side-effects.
PROGNOSIS — People with Gilbert's syndrome live normal, healthy lives comparable to the general population. In fact, some investigators have hypothesized a potential benefit from this disorder. While further study is needed, it has been suggested that the mild, chronic increased bilirubin levels may be associated with lower incidence of certain cancers. A weaker association exists with slowing of the process of hardening of the arteries, possibly because of bilirubin's antioxidant effect.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (
www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
      (
www.nlm.nih.gov/medlineplus/healthtopics.html)
British Liver Trust
         ;(
http://www.britishlivertrust.org.uk/...s_syndrome.asp)
The Canadian Liver Foundation
         ;(
www.cag-acg.org/patinfo/gilbert_s_syndrome.htm)
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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Bosma, PJ, Roy-Chowdhury, J, Bakker, C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333:1171.
2.  Powell, LW, Hemingway, E, Billing, BH, Sherlock, S. Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome). A study of 42 families. N Engl J Med 1967; 277:1108.
3. Muraca, M, Fevery, J. Influence of sex and sex steroids on bilirubin uridine diphosphate-glucuronosyl-transferase activity of rat liver. Gastroenterology 1984; 87:308.
4. de Morais, SM, Uetrecht, JP, Wells, PG. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology 1992; 102:577.
5. Carulli, N, Leon, MP, Mauro, E, et al. Alteration of drug metabolism in Gilbert's syndrome. Gut 1976; 17:581.
6. Borlak, J, Thum, T, Landt, O, et al. Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects. Hepatology 2000; 32:792.
7. Zucker, SD, Horn, PS, Sherman, KE. Serum bilirubin levels in the U.S. population: gender effect and inverse correlation with colorectal cancer. Hepatology 2004; 40:827.
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