Medicine:Gilbert's syndrome

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Gilbert's syndrome
Other namesGilbert syndrome, Meulengracht syndrome, Gilbert-Lereboullet syndrome, hyperbilirubinemia Arias type, hyperbilirubinemia type 1, familial cholemia, familial nonhemolytic jaundice[1][2]
Bilirubin.svg
Bilirubin
Pronunciation
SpecialtyGastroenterology
SymptomsUsually none, still, abdominal pain, nausea, tired and weak feeling, slight jaundice may present[1]
ComplicationsUsually none[1]
CausesGenetic[1]
Differential diagnosisCrigler–Najjar syndrome, Rotor syndrome, Dubin–Johnson syndrome[2]
TreatmentNone typically needed[1]
Frequency~5%[3]

Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority.[1] Many people never have symptoms.[1] Occasionally jaundice (a slight yellowish color of the skin or whites of the eyes) may occur.[1]

Gilbert syndrome is due to a genetic variant in the UGT1A1 gene which results in decreased activity of the bilirubin uridine diphosphate glucuronosyltransferase enzyme.[1][3] It is typically inherited in an autosomal recessive pattern and occasionally in an autosomal dominant pattern depending on the type of variant.[3] Episodes of jaundice may be triggered by stress such as exercise, menstruation, or not eating.[3] Diagnosis is based on higher levels of unconjugated bilirubin in the blood without either signs of other liver problems or red blood cell breakdown.[2][3]

Typically no treatment is needed.[1] Gilbert syndrome is associated with decreased cardiovascular health risks.[4] If jaundice is significant phenobarbital may be used, which aids in the conjugation of bilirubin.[1] Gilbert syndrome affects about 5% of people in the United States.[3] Males are more often diagnosed than females.[1] It is often not noticed until late childhood to early adulthood.[2] The condition was first described in 1901 by Augustin Nicolas Gilbert.[5][2][6]

Signs and symptoms

Jaundice

Gilbert syndrome produces an elevated level of unconjugated bilirubin in the bloodstream, but normally has no consequences. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic.[7][8] Severe cases are seen by yellowing of the skin tone and yellowing of the conjunctiva in the eye.[9]

Gilbert syndrome has been reported to contribute to an accelerated onset of neonatal jaundice. The syndrome cannot cause severe indirect hyperbilirubinemia in neonates by itself, but it may have a summative effect on rising bilirubin when combined with other factors,[10] for example in the presence of increased red blood cell destruction due to diseases such as G6PD deficiency.[11][12] This situation can be especially dangerous if not quickly treated, as the high serum bilirubin can cause irreversible neurological disability in the form of kernicterus.[13][14][15]

Detoxification of certain drugs

The enzymes that are defective in GS – UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) – are also responsible for some of the liver's ability to detoxify certain drugs. For example, Gilbert syndrome is associated with severe diarrhea and neutropenia in patients who are treated with irinotecan, which is metabolized by UGT1A1.[16]

While paracetamol (acetaminophen) is not metabolized by UGT1A1,[17] it is metabolized by one of the other enzymes also deficient in some people with GS.[18][19] A subset of people with GS may have an increased risk of paracetamol toxicity.[19][20]

Cardiovascular effects

The mild increase in unconjugated bilirubin due to Gilbert syndrome is closely related to the reduction in the prevalence of chronic diseases, especially cardiovascular disease and type 2 diabetes, related risk factors, and all-cause mortality.[21] Observational studies emphasize that the antioxidant effects of unconjugated bilirubin may bring survival benefits to patients.[22]

Several analyses have found a significantly decreased risk of coronary artery disease (CAD) in individuals with GS.[23][24]

Specifically, people with mildly elevated levels of bilirubin (1.1 mg/dl to 2.7 mg/dl) were at lower risk for CAD and at lower risk for future heart disease.[25] These researchers went on to perform a meta-analysis of data available up to 2002, and confirmed the incidence of atherosclerotic disease (hardening of the arteries) in subjects with GS had a close and inverse relationship to the serum bilirubin.[23] This beneficial effect was attributed to bilirubin IXα which is recognized as a potent antioxidant, rather than confounding factors such as high-density lipoprotein levels.[25]

This association was also seen in long-term data from the Framingham Heart Study.[26][4][non-primary source needed] Moderately elevated levels of bilirubin in people with GS and the (TA)7/(TA)7 genotype were associated with one-third the risk for both coronary heart disease and cardiovascular disease as compared to those with the (TA)6/(TA)6 genotype (i.e. a normal, nonmutated gene locus).[citation needed]

Platelet counts and MPV (mean platelet volume) are decreased in patients with Gilbert's syndrome. The elevated levels of bilirubin and decreasing levels of MPV and CRP in Gilbert's syndrome patients may have an effect on the slowing down of the atherosclerotic process.[27]

Other

Symptoms, whether connected or not to GS, have been reported in a subset of those affected: fatigue (feeling tired all the time), difficulty maintaining concentration, unusual patterns of anxiety, loss of appetite, nausea, abdominal pain, loss of weight, itching (with no rash), and others,[28] such as humor change or depression. But scientific studies found no clear pattern of adverse symptoms related to the elevated levels of unconjugated bilirubin in adults. However, other substances glucuronidized by the affected enzymes in those with Gilbert's syndrome could theoretically, at their toxic levels, cause these symptoms.[29][30] Consequently, debate exists about whether GS should be classified as a disease.[29][31] However, Gilbert syndrome has been linked to an increased risk of gallstones.[28][32]

Cause

Mutations in the UGT1A1 gene lead to Gilbert Syndrome.[33] The gene provides instructions for making the bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme, which can be found in the liver cells and is responsible for preparing bilirubin for removal from the body.[34]

The bilirubin-UGT enzyme performs a chemical reaction called glucuronidation. Glucuronic acid is transferred to unconjugated bilirubin, which is a yellowish pigment made when your body breaks down old red blood cells,[35] and then being converted to conjugated bilirubin during the reaction. Conjugated bilirubin passes from the liver into the intestines with bile. It's then excreted in stool.

People with Gilbert syndrome have approximately 30 percent of normal bilirubin-UGT enzyme function, which contributes to a lower rate of glucuronidation of unconjugated bilirubin. This substance then accumulates in the body, causing mild hyperbilirubinemia.[34]

Genetics

Gilbert syndrome is a phenotypic effect, mostly associated with increased blood bilirubin levels, but also sometimes characterized by mild jaundice due to increased unconjugated bilirubin, that arises from several different genotypic variants of the gene for the enzyme responsible for changing bilirubin to the conjugated form.[citation needed]

Gilbert's syndrome is characterized by a 70–80% reduction in the glucuronidation activity of the enzyme (UGT1A1). The UGT1A1 gene is located on human chromosome 2.[36]

More than 100 polymorphisms of the UGT1A1 gene are known, designated as UGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of its promoter region. UGT1A1 is associated with a TATA box promoter region; this region most commonly contains the genetic sequence A(TA)6TAA; this variant accounts for about 50% of alleles in many populations. However, several allelic polymorphic variants of this region occur, the most common of which results from adding another dinucleotide repeat TA to the promoter region, resulting in A(TA)7TAA, which is called UGT1A1*28; this common variant accounts for about 40% of alleles in some populations, but is seen less often, around 3% of alleles, in Southeast and East Asian people and Pacific Islanders.[citation needed]

In most populations, Gilbert syndrome is most commonly associated with homozygous A(TA)7TAA alleles.[37][38][39] In 94% of GS cases, two other glucuronosyltransferase enzymes, UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective), are also affected.[citation needed]

However, Gilbert syndrome can arise without TATA box promoter polymorphic variants; in some populations, particularly healthy Southeast and East Asians, Gilbert's syndrome is more often a consequence of heterozygote missense mutations (such as Gly71Arg also known as UGT1A1*6, Tyr486Asp also known as UGT1A1*7, Pro364Leu also known as UGT1A1*73) in the actual gene coding region,[20] which may be associated with significantly higher bilirubin levels.[20]

Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as a minor inborn error of metabolism.[citation needed]

Diagnosis

People with GS predominantly have elevated unconjugated bilirubin, while conjugated bilirubin is usually within the normal range or is less than 20% of the total. Levels of bilirubin in GS patients are reported to be from 20 μM to 90 μM (1.2 to 5.3 mg/dl)[38] compared to the normal amount of < 20 μM. GS patients have a ratio of unconjugated/conjugated (indirect/direct) bilirubin commensurately higher than those without GS.[citation needed]

The level of total bilirubin is often further increased if the blood sample is taken after fasting for two days,[40] and a fast can, therefore, be useful diagnostically. A further conceptual step that is rarely necessary or appropriate is to give a low dose of phenobarbital:[41] the bilirubin will decrease substantially.

Tests can also detect DNA variants of UGT1A1 by polymerase chain reaction or DNA fragment sequencing.[citation needed]

Differential diagnosis

While Gilbert syndrome is considered harmless, it is clinically important because it may give rise to a concern about a blood or liver condition, which could be more dangerous. However, these conditions have additional indicators:[citation needed]

Treatment

Typically no treatment is needed.[1] If jaundice is significant phenobarbital may be used.[1]

Research directions

Vitamin levels

Studies conducted so far suggest that subjects with GS may have lower levels of vitamin D and folic acid than control subjects, having these levels inversely correlated with bilirubin levels. It may be that GS may impair the metabolism or absorption of these vitamins, or that these vitamins may affect the expression or activity of the UGT1A1 enzyme that is responsible for bilirubin conjugation. However, these studies had limitations, such as the small sample size, the lack of a standardized definition of GS, the possible confounding factors of diet, lifestyle, and medication use, and the cross-sectional and observational design that does not allow for causal inference.[43]

The role of bilirubin in health and disease

Ongoing studies suggest that mild hyperbilirubinaemia in GS may have beneficial effects, probably due to the antioxidant and anti-inflammatory properties of bilirubin. Hyperbilirubinaemia in GS may protect against oxidative stress and inflammation-related diseases, such as cardiovascular diseases, cancers, diabetes, and neurodegenerative disorders. However, the mechanisms and pathways of bilirubin protection are not fully elucidated, and the optimal level and range of bilirubin are unknown. The genetic and environmental factors that influence UGT1A1 expression and activity are also poorly characterized and may affect the variability and penetrance of GS.[44] Despite the fact that hyperbilirubinemia in GS is associated with reduced incidence of cardiovascular diseases,[45] diabetes, and metabolic syndrome,[46] the clinical significance and implications of these GS research findings are unclear, and can not yet be translated into preventive or therapeutic strategies.[44]

History

Gilbert syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901.[6][5] In German literature, it is commonly associated with Jens Einar Meulengracht.[47]

Alternative, less common names for this disorder include:[citation needed]

  • Familial benign unconjugated hyperbilirubinaemia
  • Constitutional liver dysfunction
  • Familial non-hemolytic non-obstructive jaundice
  • Icterus intermittens juvenilis
  • Low-grade chronic hyperbilirubinemia
  • Unconjugated benign bilirubinemia

Society and culture

Notable cases

  • Napoleon[48]
  • Arthur Kornberg, Nobel laureate in Physiology or Medicine, 1959[49]
  • Nicky Wire, Manic Street Preachers bassist[50]
  • Alexandr Dolgopolov (tennis player)[51]
  • Jonas Folger, MotoGP rider.[52]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 "Gilbert syndrome" (in en). 2016. https://rarediseases.info.nih.gov/diseases/6507/gilbert-syndrome. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Gilbert Syndrome". 2015. https://rarediseases.org/rare-diseases/gilbert-syndrome/. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Gilbert syndrome" (in en). 27 June 2017. https://ghr.nlm.nih.gov/condition/gilbert-syndrome. 
  4. ↑ 4.0 4.1 Bulmer, A. C.; Verkade, H. J.; Wagner, K.-H. (April 2013). "Bilirubin and beyond: a review of lipid status in Gilbert's syndrome and its relevance to cardiovascular disease protection". Progress in Lipid Research 52 (2): 193–205. doi:10.1016/j.plipres.2012.11.001. ISSN 1873-2194. PMID 23201182. 
  5. ↑ 5.0 5.1 "La cholémie simple familiale". La Semaine Médicale 21: 241–3. 1901. 
  6. ↑ 6.0 6.1 "Whonamedit – dictionary of medical eponyms" (in en). http://www.whonamedit.com/synd.cfm/2877.html. 
  7. ↑ Kasper et al., Harrison's Principles of Internal Medicine, 16th edition, McGraw-Hill 2005
  8. ↑ Boon et al., Davidson's Principles & Practice of Medicine, 20th edition, Churchill Livingstone 2006
  9. ↑ Philadelphia, The Children's Hospital of (2014-08-23). "Hyperbilirubinemia and Jaundice" (in en). https://www.chop.edu/conditions-diseases/hyperbilirubinemia-and-jaundice. 
  10. ↑ Saki, F.; Hemmati, F.; Haghighat, M. (2011). "Prevalence of Gilbert syndrome in parents of neonates with pathologic indirect hyperbilirubinemia". Annals of Saudi Medicine 31 (2): 140–4. doi:10.4103/0256-4947.77498. PMID 21403409. 
  11. ↑ "Gilbert syndrome accelerates development of neonatal jaundice". Journal of Pediatrics 132 (4): 656–60. 1998. doi:10.1016/S0022-3476(98)70356-7. PMID 9580766. 
  12. ↑ "The interaction between Gilbert's syndrome and G6PD deficiency influences bilirubin levels". British Journal of Haematology 104 (4): 928–9. 1999. doi:10.1111/j.1365-2141.1999.1331a.x. PMID 10192462. 
  13. ↑ Usman, Fatima; Diala, Udochukwu; Shapiro, Steven; Le Pichon, Jean-Baptiste; Slusher, Tina (2018). "Acute bilirubin encephalopathy and its progression to kernicterus: current perspectives". Research and Reports in Neonatology 8: 33–44. doi:10.2147/RRN.S125758. https://www.dovepress.com/acute-bilirubin-encephalopathy-and-its-progression-to-kernicterus-curr-peer-reviewed-article-RRN. 
  14. ↑ Rennie, Janet M.; Beer, Jeanette; Upton, Michele (2019). "Learning from claims: hyperbilirubinaemia and kernicterus". Archives of Disease in Childhood - Fetal and Neonatal Edition 104 (2): F202–F204. doi:10.1136/archdischild-2017-314622. PMID 29802103. PMC 6580733. https://fn.bmj.com/content/104/2/F202. 
  15. ↑ Reddy, D. K.; Pandey, S. (2021). Kernicterus. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK559120/. 
  16. ↑ "UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer". Br J Cancer 91 (4): 678–82. 2004. doi:10.1038/sj.bjc.6602042. PMID 15280927. 
  17. ↑ "Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype". Int J Clin Pharmacol Ther 42 (2): 73–7. 2004. doi:10.5414/cpp42073. PMID 15180166. 
  18. ↑ "Frequent co-occurrence of the TATA box mutation associated with Gilbert's syndrome (UGT1A1*28) with other polymorphisms of the UDP-glucuronosyltransferase-1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians". Biochem Pharmacol 65 (9): 1521–7. 2003. doi:10.1016/S0006-2952(03)00074-1. PMID 12732365. 
  19. ↑ 19.0 19.1 "Heterogeneity of paracetamol metabolism in Gilbert's syndrome". European Journal of Drug Metabolism and Pharmacokinetics 24 (1): 9–13. 1999. doi:10.1007/BF03190005. PMID 10412886. 
  20. ↑ 20.0 20.1 20.2 Gilbert Syndrome at eMedicine
  21. ↑ Wagner, K. H.; Shiels, R. G.; Lang, C. A.; Seyed Khoei, N.; Bulmer, A. C. (2018). "Diagnostic criteria and contributors to Gilbert's syndrome". Critical Reviews in Clinical Laboratory Sciences 55 (2): 129–139. doi:10.1080/10408363.2018.1428526. PMID 29390925. 
  22. ↑ King, D.; Armstrong, M. J. (2019). "Overview of Gilbert's syndrome". Drug and Therapeutics Bulletin 57 (2): 27–31. doi:10.1136/dtb.2018.000028. PMID 30709860. https://pubmed.ncbi.nlm.nih.gov/30709860. 
  23. ↑ 23.0 23.1 Ladislav Novotnýc; Libor Vítek (2003). "Inverse Relationship Between Serum Bilirubin and Atherosclerosis in Men: A Meta-Analysis of Published Studies". Experimental Biology and Medicine 228 (5): 568–571. doi:10.1177/15353702-0322805-29. PMID 12709588. 
  24. ↑ Schwertner Harvey A; Vítek Libor (May 2008). "Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin". Atherosclerosis 198 (1): 1–11. doi:10.1016/j.atherosclerosis.2008.01.001. PMID 18343383. https://zenodo.org/record/1258770. 
  25. ↑ 25.0 25.1 Vítek L et al. (2002). "Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels". Atherosclerosis 160 (2): 449–56. doi:10.1016/S0021-9150(01)00601-3. PMID 11849670. 
  26. ↑ Lin JP et al. (2006). "Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study". Circulation 114 (14): 1476–81. doi:10.1161/CIRCULATIONAHA.106.633206. PMID 17000907. 
  27. ↑ Kundur, Avinash R.; Singh, Indu; Bulmer, Andrew C. (March 2015). "Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection in Gilbert's syndrome?". Atherosclerosis 239 (1): 73–84. doi:10.1016/j.atherosclerosis.2014.12.042. ISSN 1879-1484. PMID 25576848. 
  28. ↑ 28.0 28.1 GilbertsSyndrome.com
  29. ↑ 29.0 29.1 "Gilbert's syndrome—does it exist? A study of the prevalence of symptoms in Gilbert syndrome". Acta Medica Scandinavica 224 (5): 485–490. 1988. doi:10.1111/j.0954-6820.1988.tb19615.x. PMID 3264448. 
  30. ↑ "Does Gilbert's disease exist?". Lancet 1 (8018): 931–3. 1977. doi:10.1016/S0140-6736(77)92226-7. PMID 67389. 
  31. ↑ Larissa K. F. Temple; Robin S. McLeod; Steven Gallinger; James G. Wright (2001). "Defining Disease in the Genomics Era". Science Magazine 293 (5531): 807–808. doi:10.1126/science.1062938. PMID 11486074. 
  32. ↑ "Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis". Blood 94 (7): 2259–62. October 1999. doi:10.1182/blood.V94.7.2259.419k42_2259_2262. PMID 10498597. http://bloodjournal.hematologylibrary.org/cgi/pmidlookup?view=long&pmid=10498597. 
  33. ↑ "Gilbert Syndrome" (in en-US). https://rarediseases.org/rare-diseases/gilbert-syndrome/. 
  34. ↑ 34.0 34.1 "Gilbert syndrome: MedlinePlus Genetics" (in en). https://medlineplus.gov/genetics/condition/gilbert-syndrome/. 
  35. ↑ "Gilbert's syndrome - Symptoms and causes" (in en). https://www.mayoclinic.org/diseases-conditions/gilberts-syndrome/symptoms-causes/syc-20372811. 
  36. ↑ "Entrez Gene: UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54658. 
  37. ↑ "Association of human liver bilirubin UDP-glucuronyltransferase activity, most commonly due to a polymorphism in the promoter region of the UGT1A1 gene". Journal of Hepatology 33 (3): 348–351. 2000. doi:10.1016/S0168-8278(00)80268-8. PMID 11019988. 
  38. ↑ 38.0 38.1 Bosma PJ et al. (1995). "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome". New England Journal of Medicine 333 (18): 1171–5. doi:10.1056/NEJM199511023331802. PMID 7565971. 
  39. ↑ "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome". Lancet 347 (9001): 578–81. 1996. doi:10.1016/S0140-6736(96)91273-8. PMID 8596320. 
  40. ↑ J L Gollan; C Bateman; B H Billing (1976). "Effect of dietary composition on the unconjugated hyperbilirubinaemia of Gilbert's syndrome". Gut 17 (5): 335–340. doi:10.1136/gut.17.5.335. PMID 1278716. 
  41. ↑ N Carulli; M Ponz de Leon; E Mauro; F Manenti; A Ferrari (1976). "Alteration of drug metabolism in Gilbert's syndrome". Gut 17 (8): 581–587. doi:10.1136/gut.17.8.581. PMID 976795. 
  42. ↑ Singh, A.; Koritala, J.; Jialal, I. (20 May 2023). "Unconjugated Hyperbilirubinemia". StatPearls. Treasure Island, Florida: StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK549796/. Retrieved 21 December 2023. 
  43. ↑ "The frequency, clinical course, and health related quality of life in adults with Gilbert's syndrome: a longitudinal study". BMC Gastroenterol 19 (1): 22. February 2019. doi:10.1186/s12876-019-0931-2. PMID 30717703. 
  44. ↑ 44.0 44.1 "Gilbert's syndrome revisited". J Hepatol 79 (4): 1049–1055. October 2023. doi:10.1016/j.jhep.2023.06.004. PMID 37390966. 
  45. ↑ "A New Look at Gilbert Syndrome (Literature Review)" (in Russian). Georgian Med News (296): 75–81. November 2019. PMID 31889709. 
  46. ↑ "Bilirubin as a Therapeutic Molecule: Challenges and Opportunities". Antioxidants 10 (10): 1536. September 2021. doi:10.3390/antiox10101536. PMID 34679671. 
  47. ↑ Jens Einar Meulengracht at Who Named It?
  48. ↑ Foulk, WT; Butt, HR; Owen, CA Jr; Whitcomb, FF Jr; Mason, HL (1959). "Constitutional hepatic dysfunction (Gilbert's disease): its natural history and related syndromes". Medicine (Baltimore) 38 (1): 25–46. doi:10.1097/00005792-195902000-00002. PMID 13632313. 
  49. ↑ Shmaefsky, Brian (2006). "5". Biotechnology 101. Greenwood Publishing Group. pp. 175. ISBN 978-0-313-33528-0. https://books.google.com/books?id=E4KhutqTYNAC&q=%22Arthur%20Kornberg%22%20gilbert&pg=PA175. 
  50. ↑ "Wire preaches delights of three cliffs". South Wales Evening Post: p. 3. 2007-04-27. 
  51. ↑ David Cox. (19 April 2014). "A Tennis Player Learns to Be Aggressive for Health's Sake". New York Times (Monte Carlo). https://www.nytimes.com/2014/04/20/sports/tennis/tennis-roundup.html. 
  52. ↑ Khorounzhiy, Valentin (2017-11-09). "Illness that 'shut down' Tech3 MotoGP rookie Jonas Folger diagnosed". Motorsport Network. https://www.autosport.com/motogp/news/132907/illness-that-hut-down-folger-diagnosed. "After visiting specialists in his native Germany, Folger has been diagnosed with Gilbert's syndrome – a genetic ailment that precludes the liver from correctly processing bilirubin." 

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