Biomedical Engineering Reference
In-Depth Information
jaundiced, and generally survive into adulthood without neurologic
or intellectual impairment, although bilirubin encephalopathy may
develop later in life [32,38].
12.6
Gilbert's Syndrome
Mutations in the UGT1A1 gene are also responsible for the more
common and mild hyperbilirubinemia known as Gilbert's syndrome
that is found in 3- 7% of the U.S. population [41]. In contrast to a normal
UGT1A1 gene which has a promoter region TATA box containing
the genetic subsequence (TA)
TATA Gilbert's syndrome is most
commonly associated with homozygous (TA)
6
TATA alleles, referred to
as UGT1A1*28 as previously described [6,7,12,42,45]. This leads to a
70% reduction in UGT1A1 activity [43,44]. This reduction in enzyme
activity leads to an elevated level of unconjugated bilirubin in the
bloodstream, however serum bilirubin concentrations rarely exceed
5 mg/dL and usually fluctuate between 1.3 and 3 mg/dL [38]. There
are normally no serious consequences associated with this disease;
mild jaundice may appear under conditions of exertion, stress, fasting,
and infections, but the condition is otherwise usually asymptomatic.
Thus Gilbert's syndrome is considered an entirely benign and
clinically inconsequential entity, requiring neither treatment nor
long-term medical attention, although the mild hyperbilirubinemia
that occurs is sometimes mistaken for a sign of occult, chronic,
or progressive liver disease [45]. Gilbert's syndrome is generally
considered to be an autosomal recessive disorder. However, some
cases of heterozygosity and compound heterozygosity have been
reported in patients with Gilbert syndrome, predominantly among
the Asian population [33].
7
12.7
Conclusion
Irinotecan is now regarded as the most active drug for the treatment
of colorectal cancer [3]. However, one of the most difficult issues that
face oncologists is deciding the optimal dosage for therapy, as each
individual shows different outcomes even at the same dose in regard
to treatment-related adverse events, which range from no toxicity
to a lethal event. Thus the identification of predictive markers in
irinotecan therapy has been a significant goal of pharmacogenetic
