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Date of
Publication: April 9th, 2006
Written by:
Shahdad Azmoon, MD
Gilbert's
syndrome is a genetic disorder resulting in excess of a substance known as
bilirubin. Bilirubin is mainly produced from the breakdown of hemoglobin
which exists in red blood cells. Red blood cells may breakdown due to
their life span (approximately 120 days) or secondary to red blood cell
trauma. Within the liver bilirubin is usually converted into a
form which is more water soluble and that can be excreted via stool (unconjugated
transformed into conjugated bilirubin via a process called glucoronidation
also known as glucuronic acid conjugation). Accumulation of unconjugated
bilirubin may cause yellowing of the skin or eyes. Patients with
Gilbert’s syndrome usually have two abnormal genes (one from mother and
one from father) which accounts for approximately 9 percent of the general
population. (4) However even patients with a single abnormal gene may
have elevated levels of unconjugated bilirubin. (4) Approximately 30
percent of the general population is heterozygous (single abnormal gene)
for Gilbert's syndrome.) (4) It is also important to note that not all
persons with two abnormal genes will develop Gilbert's syndrome. (4) Most
patients with Gilbert's syndrome do not have any symptoms and the disorder
may have been diagnosed by coincidence when lab tests may have been done
for another reason. Males tend to get diagnosed more frequently than
women, since produce higher levels of bilirubin in general. (16)
Diagnosis is more common after puberty when the production of bilirubin
also increases. (16) Bilirubin levels can fluctuate in different people
with Gilbert's syndrome. Situations such as infections, certain drugs (Irinotecan,
tolbutamide, and acetaminophen), prolonged fasting, and/or other forms of
stress on the body may cause an elevation of the unconjugated bilirubin in
the blood (7-10). Tests which may help with the diagnosis of Gilbert's
syndrome may include blood tests, liver ultrasound, and/or caloric
deprivation test where bilirubin is increased after calorie restriction.
(7-8) A presumptive diagnosis can be made when a patient is noted to have
elevated unconjugated bilirubin for greater than one year in the setting
of normal liver function tests otherwise. Although genetic testing
can confirm the diagnosis it is not widely available. In the United
States one such laboratory to include such genetic tests is associated
with the University of Chicago. Fortunately no specific therapy is
required for patients with Gilbert's syndrome. Patients should consult
their doctor when taking new medications to be counseled on possible
increased side affects (even with some over the counter medications,
including acetaminophen.) (9) Although some investigators have
hypothesized a potential benefit associated with chronic mildly increased
bilirubin most patients with Gilbert's syndrome live comparable to people
who do not have Gilbert's syndrome. (11-12) The possible benefits of the
increased bilirubin maybe related to antioxidant effects which has
been associated with lower incidence of certain cancers as well as
slowing the process of atherogenesis. (11-13)
References
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Gilbert A, Lereboullet P. La
cholémie simple familiale. Semaine Med 1901;21:241-3
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Powell LW, Hemingway E, Billing BH, Sherlock S.
Idiopathic unconjugated hyperbilirubinemia (Gilbert’s syndrome): a study
of 42 families. N Engl J Med 1967;277:1108-1112
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Owens D, Evans J. Population studies on Gilbert’s
syndrome. J Med Genet 1975;12:152-156
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Black M, Billing BH. Hepatic bilirubin UDP-glucuronyl
transferase activity in liver disease and Gilbert’s syndrome. N Engl J
Med 1969;280:1266-1271
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Bosma, PJ,
Chowdhury, JR, 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
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Fevery J, Blanckaert N, Heirwegh
KPM, Preaux A-M, Berthelot P. Unconjugated bilirubin and an increased
proportion of bilirubin monoconjugates in the bile of patients with
Gilbert’s syndrome and Crigler-Najjar disease. J Clin Invest
1977;60:970-979
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TA, Maisels MJ, Carlson DE, Conrad ME. Effect of low caloric diet on
endogenous carbon monoxide production: normal adults and Gilbert’s
syndrome. Proc Soc Exp Biol Med 1973;144:417-419
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Felsher, BF, Rickard, D, Redeker,
AG. The reciprocal relation between caloric intake and the degree of
hyperbilirubinemia in Gilbert's syndrome. N Engl J Med 1970; 283:170.
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De Morais, SM, Uetrecht, JP, Wells, PG. Decreased
glucuronidation and increased bioactivation of acetaminophen in
Gilbert's syndrome. Gastroenterology 1992; 102:577
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Carulli, N, Leon, MP, Mauro, E, et
al. Alteration of drug metabolism in Gilbert's syndrome. Gut 1976;
17:581
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Zucker SD, Horn PS, Serman 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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Temme, EH, Zhang, J, Schouten, EG,
Kesteloot, H. Serum bilirubin and 10-year mortality risk in a Belgian
population. Cancer Causes Control 2001; 12:887
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Beutler, E, Gelbart, T, Demina, A.
Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1)
promoter: A balanced polymorphism for regulation of bilirubin
metabolism?. Proc Natl Acad Sci U S A 1998; 95:8170.
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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
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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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Muraca, M, Fevery, J. Influence of
sex and sex steroids on bilirubin uridine
diphosphate-glucuronosyl-transferase activity of rat liver.
Gastroenterology 1984; 87:308
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