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Does elevated bilirubin aid weight control by preventing development of hypothalamic leptin resistance?
  1. James J DiNicolantonio1,
  2. Mark McCarty2 and
  3. James OKeefe1
  1. 1 Preventive Cardiology, Mid America Heart Institute, Kansas City, Missouri, USA
  2. 2 Catalytic Longevity, Encinitas, California, USA
  1. Correspondence to Dr James J DiNicolantonio; jjdinicol{at}gmail.com

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Gilbert syndrome is associated with lower gain in fat mass during later life

Gilbert syndrome (GS) is characterised by a lifelong genetically determined elevation of plasma unconjugated bilirubin levels.1 This typically entails decreased hepatic expression of the enzyme that conjugates free bilirubin to glucuronic acid, uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1); this decreased activity reflects homozygosity for variant alleles in which promoter mutations decrease but do not eliminate transcription. In addition, genetic upregulation of bilirubin production—reflecting upregulation of haem oxygenase activity or increased haem synthesis—also contributes to the elevation of unconjugated bilirubin observed in subjects with GS.1–3 Diagnosis of GS generally requires a plasma bilirubin of 20 µM or above—alternatively, 1.2 mg/dL—but this diagnosis is not entirely objective, as non-genetic factors such as fasting status, gastrointestinal motility, enterohepatic bilirubin reabsorption/secretion and degree of light exposure can cause bilirubin levels to vary considerably over time. Moreover, many individuals carrying genetic variants which decrease hepatic UGT1A1 activity maintain plasma bilirubin levels below the cut-off limits for GS diagnosis; these variants alone are not sufficient to guarantee a GS diagnosis. In any case, the key point to recognise is that tissues of properly diagnosed subjects with GS are exposed to quite significantly elevated unconjugated bilirubin levels over the course of their lives.

A recent cross-sectional epidemiological study evaluating subjects with GS has achieved some remarkable findings.4 This study enrolled 124 subjects with GS (average plasma unconjugated bilirubin 30.7 µM) and 124 age-matched and gender-matched controls (8.7 µM). This study was unique in that it segregated the groups by age; subjects under and over age 35 were analysed separately. One of the most striking findings was this: whereas among the subjects under 35 body mass index (BMI) was only slightly but significantly lower in the GS group (22.5 vs 23.5, p<0.05), among those over 35 there was a large disparity: 23.8 vs 27.2 (p<0.001). The difference …

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