Introduction
Gilbert syndrome is a prevalent genetic condition affecting how the liver processes bilirubin. As an autosomal recessive disorder, it leads to mild to moderate unconjugated hyperbilirubinemia, often manifesting as recurrent jaundice episodes. For those with Gilbert syndrome, the prognosis is typically excellent, and the condition itself doesn’t cause significant liver damage. However, it’s crucial to note that these individuals might face a heightened risk of drug toxicity when exposed to medications that interfere with bilirubin metabolism. Accurate Gilbert Disease Diagnosis is therefore essential for informed patient care and management, especially in the context of medication prescriptions and potential triggers.
Patients diagnosed with Gilbert syndrome usually present with normal liver function tests, except for elevated levels of unconjugated bilirubin. The condition is generally asymptomatic and often requires no treatment. However, certain factors like fasting, illness, menstruation, and dehydration can trigger noticeable symptoms. Gilbert disease diagnosis primarily involves excluding other potential causes of hyperbilirubinemia, ensuring that patients receive the correct assessment and guidance.
This guide for automotive technicians—who, while not medical professionals, often encounter individuals and need a broad understanding of common health conditions—aims to review the etiology, epidemiology, pathophysiology, clinical presentation, evaluation, and management of Gilbert syndrome. Understanding Gilbert disease diagnosis and its implications can be valuable in a variety of professional and personal contexts.
Objectives:
- Recognize the clinical indicators and triggers of mild unconjugated hyperbilirubinemia in individuals with Gilbert syndrome.
- Differentiate Gilbert syndrome from other causes of jaundice and hyperbilirubinemia through understanding of clinical and laboratory assessments relevant to Gilbert disease diagnosis.
- Appreciate the targeted diagnostic approach used to rule out other hepatic disorders without resorting to excessive and unnecessary testing in Gilbert disease diagnosis.
- Understand the importance of appropriate care coordination for individuals with Gilbert syndrome to improve their quality of life, even though direct interprofessional team strategies are more relevant in clinical settings.
Etiology of Gilbert Syndrome
Several triggers can precipitate unconjugated hyperbilirubinemia and jaundice in individuals with Gilbert syndrome. Common precipitants include fasting, hemolytic reactions, febrile illnesses, menstruation, and physical exertion. Reducing daily caloric intake significantly, to around 400 kcal, can lead to a 2- to 3-fold increase in bilirubin levels within just 48 hours. Similarly, a comparable rise in bilirubin can occur even with an average-calorie diet if it lacks lipid supplementation. These factors are important to consider when evaluating potential triggers after a Gilbert disease diagnosis.
Typically, bilirubin levels return to normal within 12 to 24 hours of resuming a normal diet. Several theories attempt to explain unconjugated hyperbilirubinemia following dietary changes. These include increased bilirubin cycling through enterohepatic circulation, decreased conjugation due to reduced levels of uridine 5′-diphospho-glucuronosyltransferase-glucuronic acid (a crucial cosubstrate in glucuronidation), and the release of bilirubin from fat cells. Understanding these etiological factors is crucial for contextualizing a Gilbert disease diagnosis and managing patient expectations.
Epidemiology of Gilbert Syndrome
Gilbert syndrome exhibits a prevalence rate ranging from 4% to 16%, with notable variations based on ethnic ancestry. Among White populations, the prevalence is estimated to be between 2% and 10%. In Japan and East Asia, the prevalence is approximately 2%, while in India, Southern Asia, and the Middle East, rates can reach as high as 20%. These epidemiological differences highlight the genetic component of Gilbert disease diagnosis.
Clinical manifestations of Gilbert syndrome typically emerge during early adolescence and are more frequently observed in males. This gender disparity is likely due to differences in sex steroid concentrations and higher bilirubin production in males. Most diagnoses of Gilbert syndrome occur around puberty, coinciding with increased hemoglobin turnover and steroid hormone-induced inhibition of bilirubin glucuronidation. Therefore, age and sex are important demographic factors in considering a Gilbert disease diagnosis.
Pathophysiology of Gilbert Syndrome
Gilbert syndrome is inherited as an autosomal recessive condition. In individuals of White descent, it is most commonly linked to the homozygous polymorphism A(TA)7TAA in the promoter region of UGT1A1 (uridine diphosphoglucoronate-glucuronosyltransferase 1A1). This genetic variation significantly diminishes the glucuronidation of bilirubin. Specifically, homozygosity for a defect in the TATA box within the UGT1A1 promoter region results in a mutation known as UGT1A1*28. This molecular defect involves the insertion of an additional dinucleotide sequence (TA), changing the transcription initiation sequence from A(TA)6TAA to A(TA)7TAA. This genetic basis is fundamental to understanding Gilbert disease diagnosis at a molecular level.
In patients with Gilbert syndrome, UGT1A1 activity is reduced to only 30% to 50% of normal levels. Consequently, monoconjugated bile pigments are increased by about 34% in this patient group. Individuals who are heterozygous for this mutation may also exhibit serum bilirubin values higher than the general population. However, it’s important to note that not all homozygous individuals with the promoter mutation will develop clinically apparent Gilbert syndrome, indicating that other factors, such as sex, may influence clinical expression. In individuals of Asian ancestry with Gilbert syndrome, the UG1A1*28 mutation is less common. Instead, decreased expression of UGT1A1 is thought to result from variants in the gene’s coding regions. This genetic heterogeneity is a key consideration in the comprehensive Gilbert disease diagnosis process.
Gilbert syndrome represents a spectrum of disease activity, reflected by the varying degrees of impaired UGT1A1 activity. Over 100 mutations have been associated with Gilbert Syndrome, with different frequencies observed across different ethnic groups. This genetic diversity underscores why genetic testing alone is not sufficient for a definitive Gilbert disease diagnosis.
Histopathology in Gilbert Syndrome
A liver biopsy is generally not necessary for patients suspected of having Gilbert syndrome unless there are other confounding diagnoses that need to be considered. If a liver biopsy is performed, it typically shows normal histology. However, nonspecific lipofuscin pigment within the centrilobular region of the biopsy has been reported in some cases. The absence of significant histopathological abnormalities is a characteristic feature that supports Gilbert disease diagnosis and helps rule out other liver pathologies.
Toxicokinetics and Gilbert Syndrome
UGT1A1 plays a crucial role in the metabolism of estrogen and various drugs through glucuronidation. Consequently, individuals with Gilbert syndrome may be more susceptible to toxicities from medications that rely on glucuronidation. Irinotecan, a chemotherapy drug, is well-known to cause toxicity in patients with Gilbert syndrome. Its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), can accumulate, leading to diarrhea and myelosuppression. Antiviral agents like atazanavir and indinavir also inhibit UGT1A1 and may induce hyperbilirubinemia. Other drugs that can suppress or compete with UGT1A1 activity include acetaminophen, tyrosine kinase inhibitors, nonsteroidal anti-inflammatory drugs, statins, ezetimibe, oxazepam, lorazepam, lamotrigine, cyclosporin A, rifampin, ethinylestradiol, buprenorphine, menthol, and tocilizumab. This heightened sensitivity to certain drugs is a vital consideration following a Gilbert disease diagnosis, especially when prescribing new medications.
History and Physical Examination for Gilbert Syndrome
Gilbert syndrome typically becomes apparent during adolescence, with males being affected more commonly than females in a ratio of approximately 3:1. Except for mild jaundice, patients are generally asymptomatic regarding liver disease. However, they may experience complaints related to the triggers mentioned earlier, such as fasting or illness. Patients with Gilbert syndrome have a higher incidence of pigmented gallstones. Underlying hemolytic reactions can lead to bilirubin overproduction and subsequent unconjugated hyperbilirubinemia. A thorough history and physical examination are crucial steps in the Gilbert disease diagnosis process.
When evaluating a patient for Gilbert Syndrome, clinicians should obtain a detailed drug history to assess for drug-induced liver injury and to identify medications that might suppress hepatic bilirubin metabolism. Family history is also important, given the genetic inheritance pattern of Gilbert syndrome. Reviewing past laboratory records, if available, can help identify patients with a history of intermittent episodes of isolated indirect hyperbilirubinemia. Clinicians must also consider other acute and chronic liver diseases based on the history and physical findings. Patients with elevated liver enzymes or incidental hepatic steatosis noted on imaging should be evaluated for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Risk factors for MASLD/MASH include diabetes, hypertension, obesity, and hyperlipidemia, as well as genetic predispositions like variants in PNPLA3, particularly common in Hispanic individuals.
Patients should be questioned about their alcohol consumption history, as significant alcohol use can lead to alcohol-related hepatitis and metabolic-alcohol-associated liver disease. Additionally, a history of intravenous drug use, blood transfusions, incarceration, tattoos, country of birth, and high-risk sexual activity should be explored, as these factors may suggest hepatitis B or C. A careful history of autoimmune diseases in the patient or family might raise suspicion for primary biliary cholangitis, primary sclerosing cholangitis, or autoimmune hepatitis. Importantly, patients with isolated Gilbert syndrome should not exhibit signs of clinically significant portal hypertension or hepatic decompensation, such as varices, ascites, or hepatic encephalopathy. This comprehensive approach to history and physical examination is essential for accurate Gilbert disease diagnosis and for differentiating it from other conditions.
Evaluation and Diagnosis of Gilbert Syndrome
Gilbert disease diagnosis is primarily based on the finding of isolated unconjugated hyperbilirubinemia, with serum total bilirubin typically below 4 mg/dL. However, bilirubin levels can fluctuate depending on exacerbating factors. Characteristically, patients will have normal complete blood count, reticulocyte count, lactate dehydrogenase, and peripheral smear results, which help rule out hemolysis. Aminotransferases and alkaline phosphatase levels are also typically normal.
Diagnostic imaging of the liver and biliary tree is generally not needed unless other diagnoses are being considered. As mentioned earlier, liver biopsy is rarely indicated unless there is suspicion of another acute or chronic liver disorder. Provocative tests like 48-hour fasting or administration of nicotinic acid, phenobarbital, or rifampin are no longer routinely used or recommended in Gilbert disease diagnosis.
Genetic testing, including assays of UGT1A1 activity and polymerase chain reaction to identify gene polymorphisms in the TATA box of UGT1A1, may be considered in cases of diagnostic uncertainty. This is particularly relevant when initiating drugs that may affect UGT1A1 activity or when family counseling is needed. If serum liver biochemistries are elevated, further investigations should be conducted to evaluate for chronic viral hepatitis, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, hemochromatosis, celiac disease, thyroid abnormalities, and alpha-1 antitrypsin deficiency. A systematic and targeted evaluation is crucial for a precise Gilbert disease diagnosis.
Treatment and Management of Gilbert Syndrome
Patients with Gilbert syndrome typically do not require treatment. Therefore, management primarily involves reassuring patients and their families that it is a benign condition that does not necessitate further intervention. However, it is crucial to counsel patients, family members, and healthcare providers about the potential increased risk of drug toxicity when individuals with Gilbert syndrome are exposed to medications that suppress or affect UGT1A1 activity. This education is a key component of post-Gilbert disease diagnosis management.
Differential Diagnosis in Gilbert Syndrome
Unconjugated Hyperbilirubinemia
When considering Gilbert disease diagnosis, it is important to differentiate it from other causes of unconjugated hyperbilirubinemia. These differential diagnoses include:
- Increased bilirubin production: Extravascular and intravascular hemolysis, resorbing hematoma, dyserythropoiesis, Wilson disease.
- Impaired hepatic bilirubin uptake: Heart failure, portosystemic shunts, certain medications, Gilbert syndrome.
- Impaired bilirubin conjugation: Gilbert syndrome, Crigler-Najjar syndrome types I and II, advanced liver disease.
Conjugated Hyperbilirubinemia
It is also important to distinguish Gilbert syndrome, which causes unconjugated hyperbilirubinemia, from conditions that lead to conjugated hyperbilirubinemia. Differential diagnoses for conjugated hyperbilirubinemia include:
- Defects of canalicular organic anion transport: Dubin-Johnson syndrome.
- Defects of sinusoidal reuptake of conjugated bilirubin: Rotor syndrome.
- Extrahepatic cholestasis: Choledocholithiasis, pancreaticobiliary malignancy, primary sclerosing cholangitis, pancreatitis, parasitic infection.
- Intrahepatic cholestasis: Viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, primary biliary cholangitis, drugs and toxins, sepsis, infiltrative diseases, parenteral nutrition, sickle cell disease, pregnancy, end-stage liver disease.
A thorough differential diagnosis process is vital to ensure accurate Gilbert disease diagnosis and to avoid misdiagnosis.
Prognosis of Gilbert Syndrome
The prognosis for patients with Gilbert syndrome is excellent. Their outcomes are generally similar to those of the general population. Interestingly, mild unconjugated hyperbilirubinemia may have potential beneficial effects, including a lower incidence of atherosclerosis, increased insulin sensitivity, decreased risk of metabolic syndrome and obesity, and a reduced incidence of autoimmune diseases, endometrial cancer, Hodgkin lymphoma, and cancer-related mortality. This benign prognosis is a reassuring aspect of Gilbert disease diagnosis.
Complications of Gilbert Syndrome
Gilbert syndrome is a benign, autosomal recessive inherited disorder of bilirubin metabolism. Patients with Gilbert syndrome are at a slightly increased risk for more severe drug interactions, the development of pigmented gallstones, and more pronounced jaundice during the neonatal period, especially in individuals with coexisting hemolytic diseases. However, patients with Gilbert syndrome are not at increased risk for progressive liver disease, hepatic decompensation, or liver-related mortality. Following a Gilbert disease diagnosis, it is important to inform patients and their families about the inherited and benign nature of the condition, and to avoid unnecessary medical testing. If there is clinical suspicion of acute or chronic liver disease based on clinical presentation or laboratory studies, further evaluation for viral, metabolic, and autoimmune liver diseases is warranted.
Consultations for Gilbert Syndrome
Primary care clinicians and associated healthcare professionals are typically capable of diagnosing and monitoring patients with Gilbert syndrome. If the Gilbert disease diagnosis is uncertain, or if patients present with findings suggestive of another liver disease, referral to a liver disease specialist for further evaluation and management is recommended.
Deterrence and Patient Education for Gilbert Syndrome
Patients with Gilbert syndrome should be educated about potential triggers that can elevate unconjugated bilirubin levels, such as fasting, intercurrent illnesses, menstruation, overexertion, hemolytic reactions, and dehydration. Avoiding these triggers may help reduce anxiety related to fluctuating bilirubin values. Patients and their families need to understand the benign nature of Gilbert syndrome, its inheritance pattern, and the fact that treatment is generally unnecessary. Emphasizing the excellent prognosis post-Gilbert disease diagnosis is crucial for patient reassurance and education.
Pearls and Other Issues in Gilbert Syndrome
Gilbert syndrome is a benign, inherited disorder of bilirubin metabolism that does not lead to progressive liver disease, hepatic decompensation, or increased mortality. However, patients with Gilbert syndrome are at an increased risk of drug toxicity when exposed to medications that suppress or affect UGT1A1 activity. Unnecessary testing should be avoided, and patients should be managed conservatively after a Gilbert disease diagnosis. Furthermore, some evidence suggests that individuals with Gilbert syndrome may experience benefits from mild elevations in plasma bilirubin levels, such as enhanced cardioprotective and antineoplastic effects.
Enhancing Healthcare Team Outcomes in Gilbert Syndrome
Gilbert syndrome may be encountered by a wide range of healthcare professionals, including primary care clinicians, advanced practice clinicians, emergency department clinicians, pediatricians, gastroenterologists, and hepatologists. All healthcare personnel should be aware of the benign nature of this disorder and its excellent prognosis. Appropriate and targeted diagnostic testing should be performed, and unnecessary testing should be avoided in Gilbert disease diagnosis.
Patients whose clinical examination or initial tests suggest another liver disease or hepatic decompensation should be referred to a gastroenterologist or hepatologist. As with any patient interaction, high-quality, patient-centered care is essential. Clear and effective communication among all clinicians involved is paramount to streamline care, enhance patient satisfaction, and improve outcomes in the context of Gilbert disease diagnosis.
Review Questions
Figure: Metabolic Pathway of Bilirubin in Liver Cells
This diagram illustrates the metabolic pathway for bilirubin within hepatocytes. Bilirubin-G represents bilirubin glucuronate, formed with uridine diphosphate glucuronic acid (UDP-GA) as a donor. This process is catalyzed by uridine diphosphate-glucuronyltransferase (UGT1A1), the enzyme deficient in Gilbert syndrome, highlighting the core issue in Gilbert disease diagnosis.
References
1.Bosma PJ. Inherited disorders of bilirubin metabolism. J Hepatol. 2003 Jan;38(1):107-17. [PubMed: 12480568]
2.Burchell B, Hume R. Molecular genetic basis of Gilbert’s syndrome. J Gastroenterol Hepatol. 1999 Oct;14(10):960-6. [PubMed: 10530490]
3.Fretzayas A, Moustaki M, Liapi O, Karpathios T. Gilbert syndrome. Eur J Pediatr. 2012 Jan;171(1):11-5. [PubMed: 22160004]
4.Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014 Jun;146(7):1625-38. [PubMed: 24704527]
5.Strauss KA, Ahlfors CE, Soltys K, Mazareigos GV, Young M, Bowser LE, Fox MD, Squires JE, McKiernan P, Brigatti KW, Puffenberger EG, Carson VJ, Vreman HJ. Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier. Hepatology. 2020 Jun;71(6):1923-1939. [PMC free article: PMC7909716] [PubMed: 31553814]
6.Muraca M, Fevery J, Blanckaert N. Relationships between serum bilirubins and production and conjugation of bilirubin. Studies in Gilbert’s syndrome, Crigler-Najjar disease, hemolytic disorders, and rat models. Gastroenterology. 1987 Feb;92(2):309-17. [PubMed: 3792767]
7.Muraca M, Blanckaert N. Liquid-chromatographic assay and identification of mono- and diester conjugates of bilirubin in normal serum. Clin Chem. 1983 Oct;29(10):1767-71. [PubMed: 6616822]
8.Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol. 2017 Jan;112(1):18-35. [PubMed: 27995906]
9.Horsfall LJ, Nazareth I, Pereira SP, Petersen I. Gilbert’s syndrome and the risk of death: a population-based cohort study. J Gastroenterol Hepatol. 2013 Oct;28(10):1643-7. [PubMed: 23701650]
10.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 Jul 23;283(4):170-2. [PubMed: 5424007]
11.Barrett PV. Hyperbilirubinemia of fasting. JAMA. 1971 Sep 06;217(10):1349-53. [PubMed: 5109641]
12.Gollan JL, Bateman C, Billing BH. Effect of dietary composition on the unconjugated hyperbilirubinaemia of Gilbert’s syndrome. Gut. 1976 May;17(5):335-40. [PMC free article: PMC1411132] [PubMed: 1278716]
13.Felsher BF, Carpio NM, VanCouvering K. Effect of fasting and phenobarbital on hepatic UDP-glucuronic acid formation in the rat. J Lab Clin Med. 1979 Mar;93(3):414-27. [PubMed: 107254]
14.Kotal P, Vítek L, Fevery J. Fasting-related hyperbilirubinemia in rats: the effect of decreased intestinal motility. Gastroenterology. 1996 Jul;111(1):217-23. [PubMed: 8698202]
15.Brink MA, Méndez-Sánchez N, Carey MC. Bilirubin cycles enterohepatically after ileal resection in the rat. Gastroenterology. 1996 Jun;110(6):1945-57. [PubMed: 8964422]
16.Raijmakers MT, Jansen PL, Steegers EA, Peters WH. Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene. J Hepatol. 2000 Sep;33(3):348-51. [PubMed: 11019988]
17.Borlak J, Thum T, Landt O, Erb K, Hermann R. Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert’s syndrome) in healthy subjects. Hepatology. 2000 Oct;32(4 Pt 1):792-5. [PubMed: 11003624]
18.Roy-Chowdhury N, Deocharan B, Bejjanki HR, Roy-Chowdhury J, Koliopoulos C, Petmezaki S, Valaes T. Presence of the genetic marker for Gilbert syndrome is associated with increased level and duration of neonatal jaundice. Acta Paediatr. 2002;91(1):100-1. [PubMed: 11883809]
19.Wagner KH, Shiels RG, Lang CA, Seyed Khoei N, Bulmer AC. Diagnostic criteria and contributors to Gilbert’s syndrome. Crit Rev Clin Lab Sci. 2018 Mar;55(2):129-139. [PubMed: 29390925]
20.Muraca M, Fevery J. Influence of sex and sex steroids on bilirubin uridine diphosphate-glucuronosyltransferase activity of rat liver. Gastroenterology. 1984 Aug;87(2):308-13. [PubMed: 6428963]
21.Kaplan M. Gilbert’s syndrome and jaundice in glucose-6-phosphate dehydrogenase deficient neonates. Haematologica. 2000;85(E-letters):E01. [PubMed: 11114816]
22.Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med. 1995 Nov 02;333(18):1171-5. [PubMed: 7565971]
23.Vítek L, Tiribelli C. Gilbert’s syndrome revisited. J Hepatol. 2023 Oct;79(4):1049-1055. [PubMed: 37390966]
24.Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr Res. 2016 Mar;79(3):378-86. [PMC free article: PMC4821713] [PubMed: 26595536]
25.SAGILD U, DALGAARD OZ, TYGSTRUP N. Constitutional hyperbilirubinemia with unconjugated bilirubin in the serum and lipochrome-like pigment granules in the liver. Ann Intern Med. 1962 Feb;56:308-14. [PubMed: 14496018]
26.Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010 Oct;24(5):555-71. [PubMed: 20955959]
27.Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest. 1998 Feb 15;101(4):847-54. [PMC free article: PMC508633] [PubMed: 9466980]
28.Burchell B, Soars M, Monaghan G, Cassidy A, Smith D, Ethell B. Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases. Toxicol Lett. 2000 Mar 15;112-113:333-40. [PubMed: 10720749]
29.Lankisch TO, Moebius U, Wehmeier M, Behrens G, Manns MP, Schmidt RE, Strassburg CP. Gilbert’s disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype. Hepatology. 2006 Nov;44(5):1324-32. [PubMed: 17058217]
30.de Morais SM, Uetrecht JP, Wells PG. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert’s syndrome. Gastroenterology. 1992 Feb;102(2):577-86. [PubMed: 1732127]
31.Carulli N, Ponz de Leon M, Mauro E, Manenti F, Ferrari A. Alteration of drug metabolism in Gilbert’s syndrome. Gut. 1976 Aug;17(8):581-7. [PMC free article: PMC1411334] [PubMed: 976795]
32.Miners JO, McKinnon RA, Mackenzie PI. Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance. Toxicology. 2002 Dec 27;181-182:453-6. [PubMed: 12505351]
33.del Giudice EM, Perrotta S, Nobili B, Specchia C, d’Urzo G, Iolascon A. Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis. Blood. 1999 Oct 01;94(7):2259-62. [PubMed: 10498597]
34.Origa R, Galanello R, Perseu L, Tavazzi D, Domenica Cappellini M, Terenzani L, Forni GL, Quarta G, Boetti T, Piga A. Cholelithiasis in thalassemia major. Eur J Haematol. 2009 Jan;82(1):22-5. [PubMed: 19021734]
35.Haverfield EV, McKenzie CA, Forrester T, Bouzekri N, Harding R, Serjeant G, Walker T, Peto TE, Ward R, Weatherall DJ. UGT1A1 variation and gallstone formation in sickle cell disease. Blood. 2005 Feb 01;105(3):968-72. [PubMed: 15388579]
36.Murphy EL, Bryzman SM, Glynn SA, Ameti DI, Thomson RA, Williams AE, Nass CC, Ownby HE, Schreiber GB, Kong F, Neal KR, Nemo GJ. Risk factors for hepatitis C virus infection in United States blood donors. NHLBI Retrovirus Epidemiology Donor Study (REDS). Hepatology. 2000 Mar;31(3):756-62. [PubMed: 10706569]
37.Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012 Mar 09;30(12):2212-9. [PubMed: 22273662]
38.Fischer HP, Goltz D. [Autoimmune liver diseases]. Pathologe. 2020 Sep;41(5):444-456. [PubMed: 32749523]
39.Vierling JM, Berk PD, Hofmann AF, Martin JF, Wolkoff AW, Scharschmidt BF. Normal fasting-state levels of serum cholyl-conjugated bile acids in Gilbert’s syndrome: an aid to the diagnosis. Hepatology. 1982 May-Jun;2(3):340-3. [PubMed: 7076117]
40.Douglas JG, Beckett GJ, Nimmo IA, Finlayson ND, Percy-Robb IW. Bile salt measurements in Gilbert’s syndrome. Eur J Clin Invest. 1981 Dec;11(6):421-3. [PubMed: 6800816]
41.Okolicsanyi L, Fevery J, Billing B, Berthelot P, Thompson RP, Schmid R, Berk PD. How should mild, isolated unconjugated hyperbilirubinemia be investigated? Semin Liver Dis. 1983 Feb;3(1):36-41. [PubMed: 6340206]
42.Klevens RM, Miller JT, Iqbal K, Thomas A, Rizzo EM, Hanson H, Sweet K, Phan Q, Cronquist A, Khudyakov Y, Xia GL, Spradling P. The evolving epidemiology of hepatitis a in the United States: incidence and molecular epidemiology from population-based surveillance, 2005-2007. Arch Intern Med. 2010 Nov 08;170(20):1811-8. [PubMed: 21059974]
43.Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson’s disease: A review of what we have learned. World J Hepatol. 2015 Dec 18;7(29):2859-70. [PMC free article: PMC4678372] [PubMed: 26692151]
44.Patel D, McAllister SL, Teckman JH. Alpha-1 antitrypsin deficiency liver disease. Transl Gastroenterol Hepatol. 2021;6:23. [PMC free article: PMC7829072] [PubMed: 33824927]
45.Fargo MV, Grogan SP, Saguil A. Evaluation of Jaundice in Adults. Am Fam Physician. 2017 Feb 01;95(3):164-168. [PubMed: 28145671]
46.Ullrich D, Sieg A, Blume R, Bock KW, Schröter W, Bircher J. Normal pathways for glucuronidation, sulphation and oxidation of paracetamol in Gilbert’s syndrome. Eur J Clin Invest. 1987 Jun;17(3):237-40. [PubMed: 3113968]
47.VanWagner LB, Green RM. Evaluating elevated bilirubin levels in asymptomatic adults. JAMA. 2015 Feb 03;313(5):516-7. [PMC free article: PMC4424929] [PubMed: 25647209]
Disclosure: Lafaine Grant declares no relevant financial relationships with ineligible companies.
Disclosure: Thomas Faust declares no relevant financial relationships with ineligible companies.
Disclosure: Viveksandeep Thoguluva Chandrasekar declares no relevant financial relationships with ineligible companies.
Disclosure: Savio John declares no relevant financial relationships with ineligible companies.
