In order to understand the pathogenesis of Gilbert's syndrome, it is necessary for a brief overview of bilirubin metabolism. As mentioned previously, disorders of bilirubin metabolism can be divided into five major categories. Of note, the secretion of bilirubin into the biliary tract is rate-limiting, and most susceptible to impairment with liver damage3—hence, most cases of liver disease will see a rise in both conjugated and uncon-jugated bilirubin.
Bilirubin is the end product of heme metabolism. The daily production of heme in healthy individuals ranges from 0.2 to 0.3 g, the majority the result of breakdown of senescent red blood cells by the mononuclear phagocyte system. The remainder of heme is derived from turnover of hepatic heme or hemoproteins and from premature destruction of newly formed red blood cells in the bone marrow. Within the phagocytic system, heme is degraded to biliverdin by heme oxygenase, then to bilirubin by biliverdin reductase. Unconjugated bilirubin is nonpolar, and must be complexed with albumin in the blood to make it water soluble for delivery to the liver.
Uptake into hepatocytes is via diffusion or facilitated transport. This involves binding of bilirubin to anion-binding proteins. This step is usually not an important point of impairment in bilirubin metabolism, although some drugs, such as rifampin, are known to interfere at this step.
Bilirubin, still in its unconjugated form at this point, is then glucuronidated, or conjugated, to make it water-soluble. This is necessary for the release and solubilizing of bilirubin in bile, as no albumin is present in bile for binding. The enzyme responsible for glucuroni-dation of bilirubin in human liver is UDP-glucuronosyltransferase (bilirubin/uridine diphosphoglucuronate-glucuronosyltransferase), or UGT. This enzyme is located in the endoplasmic reticulum. Of the two isoforms reported, only UGT1A1 contributes significantly to bilirubin glucuronidation.4,5
Conjugated bilirubin is then secreted by an energy-dependent process into bile. This process is still incompletely understood, but is the rate-limiting step in hepatic metabolism of bilirubin. Impairment in secretion is present in Rotor's and Dubin-Johnson syndromes, which present with a conjugated hyperbilirubinemia.
Excretion of conjugated bilirubin into the small intestine occurs via the biliary tract with delivery of bile to the ampulla of Vater. Any disruption of this delivery pathway by compression, blockage, or obliteration of the biliary ducts will result in bile backup, consequent reabsorption of bilirubin, and a conjugated hyperbilirubinemia.
Unconjugated hyperbilirubinemia in Gilbert's syndrome is the result of decreased hepatic glucuronidating activity. The molecular basis for Gilbert's syndrome lies in one of two types of mutations associated with the UGT1A1 gene. The first, which occurs in nearly all cases in Caucasians, is a dinucleotide polymorphism in the TATA box promoter of the UGT1A1 gene, where A(TA)7TAA replaces A(TA)6TAA.6-8 The insertion of the extra TA in the promoter decreases transcription of the gene; patients who are homozygous for the A(TA)7TAA allele have UGT1A1 production that is approximately 30% of normal.9 In the Caucasian population, the frequency of the A(TA)7TAA allele is approximately 35%; almost all Caucasian patients with Gilbert's syndrome are associated with homozygosity for this polymorphism and no associated coding mutation (discussed below).6,7 On the other hand, the frequency of this polymorphism in the Japanese population is only 11%, and only one-third of Japanese patients with Gilbert's syndrome are associated with homozygosity at this site without an associated coding mutation.
The second type of mutation, rare in Caucasians but common in Asians, is caused by missense mutations in the coding region of the UGT1A1 gene.10 Several missense mutations have been described, including G71R and P229Q.11 The possibility of coding mutations, for which a patient may be heterozygous, homozygous, or compound heterozygous, and one or both copies of the A(TA)7TAA promoter allele, allows for a range of phenotypes in this population. In addition, an additional missense mutation, Y486D, with or without the accompanying G71R mutation, has been associated with Crigler-Naijjar syndrome type II.12 It is clear that in the Asian population the range of mutations affecting the UGT1A1 gene are more diverse, the phenotypes more complex, and as of yet, the situation not fully understood.
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