Introduction
Gilbert syndrome, a frequently encountered genetic condition, intricately affects bilirubin metabolism within the liver. First characterized in the early 20th century by Gilbert, Castaigne, and Lereboulette, this autosomal recessive disorder stands as a prevalent cause of mild to moderate isolated unconjugated hyperbilirubinemia. The global prevalence of Gilbert syndrome exhibits variability, ranging from 2% to 20% across different ethnicities.[1, 2] The underlying mechanism involves impaired glucuronidation of bilirubin, leading to elevated levels of unconjugated bilirubin in the blood and manifesting as recurrent episodes of jaundice.[1] It is crucial to note that under physiological conditions, approximately 95% of bilirubin exists in its unconjugated form. While Gilbert syndrome itself typically does not necessitate treatment, accurate diagnosis is paramount to differentiate it from other disorders presenting with unconjugated hyperbilirubinemia.[3]
When evaluating patients exhibiting unconjugated hyperbilirubinemia, a broad spectrum of diagnoses must be considered. These include disorders affecting bilirubin uptake, conjugation, and overproduction, as illustrated in Figure 1. Hepatic disorders impacting uptake, storage, conjugation, and excretion can induce both unconjugated and conjugated hyperbilirubinemia.[4] Crigler-Najjar syndrome, for instance, is notably characterized by marked unconjugated hyperbilirubinemia.[5] Furthermore, conditions such as hemolytic reactions, ineffective erythropoiesis, and resorbing hematomas can trigger bilirubin overproduction, subsequently leading to unconjugated hyperbilirubinemia. Hemolytic reactions encompass a diverse array of conditions, including hereditary enzyme deficiencies, hemoglobinopathies, red blood cell membrane defects, infections, medications, toxins, warm autoimmune hemolytic anemia, paroxysmal cold hemoglobinuria, and cold agglutinin disease, all of which can contribute to elevated unconjugated bilirubin levels.[6, 7] While most individuals with Gilbert syndrome remain asymptomatic concerning liver disease, certain triggers can precipitate symptomatic episodes. These triggers, known to exacerbate unconjugated hyperbilirubinemia in Gilbert syndrome, include fasting, intercurrent illnesses, menstruation, and dehydration.[3]
Other acute and chronic liver pathologies commonly manifest with both unconjugated and conjugated hyperbilirubinemia.[8] In hepatobiliary disorders, a disproportionate rise in conjugated bilirubin is typically observed. Consequently, a thorough evaluation for viral, metabolic, and autoimmune liver disorders is essential when assessing patients with hyperbilirubinemia and jaundice. A meticulous clinical assessment, targeted laboratory investigations, and the exclusion of other differential diagnoses associated with unconjugated hyperbilirubinemia, including various acute and chronic liver diseases, are crucial steps before establishing a diagnosis of Gilbert syndrome. Once Gilbert syndrome is diagnosed, management primarily involves conservative observation.[3] The prognosis for individuals with Gilbert syndrome is generally excellent.[9]
Etiology
Several factors can precipitate unconjugated hyperbilirubinemia and jaundice in individuals with Gilbert syndrome. Common triggers include fasting, hemolytic events, febrile illnesses, menstruation, and strenuous physical exertion.[3, 10] Notably, reducing daily caloric intake to approximately 400 kcal can result in a significant 2- to 3-fold increase in bilirubin levels within a mere 48 hours.[10, 11] A similar elevation in bilirubin can also occur with an average-calorie diet lacking lipid supplementation.[12]
Typically, bilirubin levels revert to normal within 12 to 24 hours upon resumption of a regular diet. Several hypotheses have been proposed to elucidate the mechanism of unconjugated hyperbilirubinemia following dietary modifications. These include increased bilirubin cycling through enterohepatic circulation, diminished 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.[13, 14, 15]
Epidemiology
The prevalence of Gilbert syndrome varies considerably, ranging from 4% to 16% in different populations, with notable variations based on ethnic ancestry.[16, 17, 18] In Caucasian populations, prevalence estimates range from 2% to 10%. In contrast, Japan and East Asia exhibit lower prevalence rates of approximately 2%, while India, Southern Asia, and the Middle East report higher rates, reaching up to 20%.[19] Clinical manifestations often emerge during early adolescence and are observed more frequently in males.[20] This gender disparity is likely attributable to differences in sex steroid concentrations and the inherently higher bilirubin production rates in males.[20] Diagnosis frequently occurs around puberty, coinciding with increased hemoglobin turnover and the inhibitory effects of endogenous steroid hormones on bilirubin glucuronidation.[20]
Pathophysiology
Gilbert syndrome follows an autosomal recessive inheritance pattern. In individuals of Caucasian descent, Gilbert syndrome is most commonly linked to a homozygous polymorphism, A(TA)7TAA, located in the promoter region of the UGT1A1 gene (uridine diphosphoglucoronate-glucuronosyltransferase 1A1). This genetic variation leads to a substantial reduction in bilirubin glucuronidation. Homozygosity for a defect within the TATA box of the UGT1A1 promoter region results in a specific UGT1A1 mutation termed UGT1A1*28. This molecular defect involves the insertion of an additional dinucleotide sequence (TA), altering the transcription initiation sequence from A(TA)6TAA to A(TA)7TAA.[1] Consequently, UGT1A1 activity is reduced to only 30% to 50% of normal levels in individuals with Gilbert syndrome.[21]
This patient population exhibits a 34% increase in monoconjugated bile pigments.[21] Heterozygous carriers of the mutation also tend to have serum bilirubin levels higher than the general population. However, it is important to note that not all homozygous individuals with the promoter mutation will clinically manifest Gilbert syndrome, suggesting that other factors, such as sex, may play a role in phenotypic expression.[22, 23, 24] Interestingly, individuals of Asian ancestry with Gilbert syndrome are less likely to carry the UG1A1*28 mutation. In these populations, reduced UGT1A1 expression is believed to stem from variants within the gene’s coding regions.
Gilbert syndrome represents a spectrum of disease severity, reflecting varying degrees of impaired UGT1A1 activity. Over 100 mutations have been associated with Gilbert Syndrome, with ethnic-specific variations in their frequencies. This genetic heterogeneity underscores why genetic testing alone should not serve as the definitive diagnostic tool for Gilbert syndrome.
Histopathology
Liver biopsy is generally not indicated for patients suspected of having Gilbert syndrome unless there are compelling reasons to consider alternative diagnoses. In cases where liver biopsy is performed, the histological findings are typically normal. A nonspecific finding of lipofuscin pigment within the centrilobular region of the biopsy has also been reported in some cases.[25, 26]
Toxicokinetics
The UGT1A1 enzyme plays a crucial role in the metabolism of estrogen and various other drugs through glucuronidation. Consequently, individuals with Gilbert syndrome may exhibit heightened susceptibility to toxicities from medications that rely on glucuronidation for elimination. Irinotecan is a well-recognized example of a drug that can induce significant toxicity in patients with Gilbert syndrome.[27, 28] The active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), can accumulate to toxic levels, leading to adverse effects such as diarrhea and myelosuppression. Antiviral medications like atazanavir and indinavir are known to inhibit UGT1A1 activity, potentially causing hyperbilirubinemia.[29, 29] 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.[30, 31, 32, 23] Understanding these drug interactions is crucial in the clinical management of patients with Gilbert syndrome.
History and Physical Examination for Diagnosis Gilbert’s Syndrome
Gilbert syndrome typically manifests during adolescence.[20] Males are more frequently affected than females, with a reported ratio of approximately 3:1.[20] Apart from mild jaundice, patients are usually asymptomatic regarding liver disease. However, they may present with complaints related to the triggers previously mentioned.[3, 10] Notably, individuals with Gilbert syndrome have a higher incidence of pigmented gallstones.[33, 34, 35] Underlying hemolytic conditions can lead to bilirubin overproduction, potentially causing unconjugated hyperbilirubinemia.[6, 7]
When evaluating a patient for suspected Gilbert Syndrome, clinicians should obtain a detailed medical history. This includes a thorough drug history to assess for drug-induced liver injury and identify medications that may suppress hepatic bilirubin metabolism. Family history is also important, given the inherited nature of Gilbert syndrome. Reviewing past laboratory records, if available, can help identify patients with a history of intermittent episodes of isolated indirect hyperbilirubinemia. Clinicians should also consider other acute and chronic liver diseases based on the patient’s history and physical examination findings. In patients with elevated liver enzymes or incidental hepatic steatosis detected on imaging, further evaluation for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) is warranted. Key risk factors for MASLD/MASH include diabetes, hypertension, obesity, and hyperlipidemia, as well as genetic predispositions such as PNPLA3 variants, which are more prevalent in Hispanic populations.
It is also important to inquire about a history of significant alcohol consumption, which can lead to alcohol-related hepatitis and metabolic-alcohol-associated liver disease. Furthermore, history of intravenous drug use, blood transfusions, incarceration, tattoos, country of birth, and high-risk sexual activity should be elicited, as these factors may suggest hepatitis B or C infection.[36, 37] A careful assessment of personal or family history of autoimmune diseases may raise suspicion for primary biliary cholangitis, primary sclerosing cholangitis, or autoimmune hepatitis.[38] Patients with isolated Gilbert syndrome should not exhibit clinical evidence of significant portal hypertension or hepatic decompensation, such as varices, ascites, or hepatic encephalopathy.
Evaluation and Diagnosis of Gilbert’s Syndrome
Gilbert syndrome is characterized by isolated unconjugated hyperbilirubinemia, with serum total bilirubin levels typically below 4 mg/dL. However, bilirubin levels can fluctuate depending on exacerbating factors.[3] Characteristically, routine laboratory tests, including complete blood count, reticulocyte count, lactate dehydrogenase, and peripheral blood smear, are normal, excluding hemolysis.[19] Liver enzymes, such as aminotransferases and alkaline phosphatase, are also within the normal range.[39, 40, 41]
Diagnostic imaging of the liver and biliary tree is generally not necessary unless there is suspicion of an alternative diagnosis. As previously mentioned, liver biopsy is rarely indicated unless another acute or chronic liver disorder is suspected. Provocative tests, such as 48-hour fasting or administration of medications like nicotinic acid, phenobarbital, or rifampin, are no longer routinely used or recommended in the diagnostic process.
Genetic testing, including assays for UGT1A1 activity and polymerase chain reaction to detect gene polymorphisms in the TATA box of UGT1A1, may be considered in cases of diagnostic uncertainty. This is particularly relevant when initiating medications known to affect UGT1A1 activity (refer to the Toxicokinetics section for detailed information on these medications) or when genetic counseling is desired for family planning.[17] If the patient exhibits elevated serum liver biochemistries, 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.[36, 42, 43, 44]
Figure 1: Metabolic Pathway for Bilirubin in the Hepatocyte. Bilirubin-G corresponds to bilirubin glucuronate; the donor is uridine diphosphate glucuronic acid (UDP-GA). This process is catalyzed by the enzyme uridine diphosphate-glucuronyltransferase (UGT1A1). Gilbert syndrome impairs this glucuronidation step, leading to unconjugated hyperbilirubinemia.
Treatment and Management of Gilbert’s Syndrome
Typically, Gilbert syndrome does not necessitate any specific treatment.[3] Therefore, the primary management strategy involves reassuring patients and their families about the benign nature of this condition and avoiding unnecessary further investigations. However, it is crucial to educate patients, family members, and healthcare providers that individuals with Gilbert syndrome might have an increased risk of drug toxicity when exposed to medications that can suppress or affect UGT1A1 activity (refer to the Toxicokinetics section for a comprehensive list of these medications).[23]
Differential Diagnosis
Unconjugated Hyperbilirubinemia
The differential diagnosis for unconjugated hyperbilirubinemia includes several conditions:
- Increased bilirubin production: Conditions such as extravascular and intravascular hemolysis, resorbing hematoma, dyserythropoiesis, and Wilson disease.
- Impaired hepatic bilirubin uptake: Conditions such as heart failure, portosystemic shunts, certain medications, and Gilbert syndrome itself.
- Impaired bilirubin conjugation: Conditions such as Gilbert syndrome, Crigler-Najjar syndrome types I and II, and advanced liver disease.[45]
Conjugated Hyperbilirubinemia
The differential diagnosis for conjugated hyperbilirubinemia includes:
- Defects of canalicular organic anion transport: Dubin-Johnson syndrome.
- Defects of sinusoidal reuptake of conjugated bilirubin: Rotor syndrome.
- Extrahepatic cholestasis: Conditions such as choledocholithiasis, pancreaticobiliary malignancy, primary sclerosing cholangitis, pancreatitis, and parasitic infections.
- Intrahepatic cholestasis: Conditions such as viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, primary biliary cholangitis, drug and toxin-induced liver injury, sepsis, infiltrative liver diseases, parenteral nutrition, sickle cell disease, pregnancy-related cholestasis, and end-stage liver disease.[45]
Prognosis
The prognosis for patients with Gilbert syndrome is excellent.[3] Their overall life expectancy and health outcomes are similar to those of the general population. Intriguingly, mild unconjugated hyperbilirubinemia, as seen in Gilbert syndrome, may even confer some beneficial effects, including a potentially lower incidence of atherosclerosis, improved insulin sensitivity, reduced risk of metabolic syndrome and obesity, and a decreased incidence of autoimmune diseases, endometrial cancer, Hodgkin lymphoma, and cancer-related mortality.[3, 23, 3, 30, 46]
Complications
Gilbert syndrome is a benign, inherited disorder of bilirubin metabolism with an autosomal recessive pattern.[3] While it is not associated with progressive liver disease or increased liver-related mortality, patients with Gilbert syndrome may face an increased risk of certain complications. These include more severe drug interactions due to impaired UGT1A1 function, a higher likelihood of developing pigmented gallstones, and potentially more pronounced jaundice during the neonatal period, especially in individuals with coexisting hemolytic diseases.[23] It is essential to reassure patients and families about the benign and inherited nature of Gilbert syndrome and to avoid unnecessary diagnostic testing. However, if clinical findings or laboratory results raise suspicion for acute or chronic liver disease, a more comprehensive evaluation for viral, metabolic, and autoimmune liver disorders should be undertaken.
Consultations
Primary care physicians and other healthcare professionals are typically well-equipped to diagnose and manage patients with Gilbert syndrome.[47] However, in cases where the diagnosis is uncertain, or if patients present with findings suggestive of another underlying liver disease, referral to a liver disease specialist (hepatologist) is recommended for further evaluation and specialized management.
Deterrence and Patient Education for Gilbert’s Syndrome
Educating patients with Gilbert syndrome about potential triggers that can elevate unconjugated bilirubin levels is crucial. These triggers include fasting, intercurrent illnesses, menstruation, overexertion, hemolytic reactions, and dehydration.[10, 47] Advising patients to avoid these triggers can help minimize anxiety related to fluctuations in bilirubin levels. Furthermore, comprehensive patient education should emphasize the benign nature of Gilbert syndrome, its inheritance pattern, the absence of необходимости for treatment, and the excellent long-term prognosis.
Pearls and Other Important Considerations
Gilbert syndrome is a benign, inherited condition affecting bilirubin metabolism that does not lead to progressive liver disease, hepatic decompensation, or increased mortality. However, it is crucial to recognize that these patients are at increased risk of drug toxicity when exposed to medications that suppress or interfere with UGT1A1 activity. Unnecessary diagnostic testing should be avoided, and patient management should be conservative and focused on education and reassurance. Interestingly, some evidence suggests that individuals with Gilbert syndrome may potentially benefit from the cardioprotective and antineoplastic effects associated with mild elevations in plasma bilirubin levels.
Enhancing Healthcare Team Outcomes in Gilbert’s Syndrome Management
Gilbert syndrome is a condition that may be encountered across various healthcare settings, including primary care, emergency departments, and specialist clinics such as pediatrics, gastroenterology, and hepatology.[47] All healthcare personnel should be well-informed about the benign nature of Gilbert syndrome and its favorable prognosis. Appropriate and targeted diagnostic testing should be employed, while avoiding unnecessary and redundant investigations.
Patients who present with clinical signs or laboratory findings suggestive of an alternative liver disease or hepatic decompensation should be promptly referred to a gastroenterologist or hepatologist for expert evaluation. As with all patient encounters, delivering high-quality, patient-centered care is paramount. Effective communication and collaboration among all members of the healthcare team are essential to streamline care pathways, enhance patient satisfaction, and optimize overall outcomes for individuals with Gilbert syndrome.
Review Questions
[Link to Review Questions (as in original article)]
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Disclosures
[Disclosures as in original article]
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.
