para>Rare for the disorder to be diagnosed before puberty (2)
Pregnancy Considerations
The relative fasting that may occur with morning sickness can elevate bilirubin level.
EPIDEMIOLOGY
- Predominant age: present from birth but most often presents in the 2nd or 3rd decade of life; heterozygous for single abnormal gene (3)
- Predominant sex: male > female (2 to 7:1)
Prevalence
Prevalence in the United States: ~7% of the population (4); ~1 in 3 of those affected are not aware that they have the disorder.
ETIOLOGY AND PATHOPHYSIOLOGY
The hyperbilirubinemia results from impaired hepatic bilirubin clearance (~30% of normal). Hepatic bilirubin conjugation (glucuronidation) is reduced, although this is likely not the only defect (3).
Genetics
A gene defect resulting in reduced bilirubin uridine diphosphate-glucuronosyltransferase-1 appears to be necessary but not sufficient for Gilbert syndrome (5).
RISK FACTORS
Male gender
COMMONLY ASSOCIATED CONDITIONS
Gilbert disease may be part of a spectrum of hereditary disorders that includes types I and II Crigler-Najjar syndrome.
DIAGNOSIS
HISTORY
No significant symptoms, although a variety of nonspecific symptoms have been described. An episode of nonpruritic jaundice can be triggered by stressors such as fasting, dehydration, infections, physical exertion, lack of sleep, and surgery. Some medications may also trigger episodes of jaundice, such as drugs that inhibit glucuronyl transferase, such as gemfibrozil and the protease inhibitors atazanavir and indinavir. Any symptoms present during an episode of jaundice, including fatigue, are caused by the triggering factor and are not directly a result of the Gilbert disease (6).
PHYSICAL EXAM
No abnormal physical findings other than occasional mild jaundice that can be precipitated by the above-mentioned triggers (fasting, dehydration, infections, physical exertion, lack of sleep, and surgery).
DIFFERENTIAL DIAGNOSIS
- Hemolysis
- Ineffective erythropoiesis (megaloblastic anemias, certain porphyrias, thalassemia major, sideroblastic anemia, severe lead poisoning, congenital dyserythropoietic anemias)
- Cirrhosis
- Chronic persistent hepatitis
- Pancreatitis
- Biliary tract disease
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Bilirubin: Elevated but <6 mg/dL (103 μmol/L) and usually <3 mg/dL (51 μmol/L), virtually all unconjugated (indirect), with conjugated bilirubin within the normal range and/or <20% of the total bilirubin (6).
- CBC with peripheral smear is normal.
- Reticulocyte count is normal.
- Liver function tests (LFTs) (aspartate aminotransferase [AST], alanine transaminase [ALT], alkaline phosphatase, and gamma-glutamyl transpeptidase [GGT]) are normal.
- Fasting and postprandial serum bile acids are normal.
- Up to 60% of patients have clinically insignificant mild hemolysis that frequently can only be detected with sophisticated red cell survival studies.
- Drugs that may alter lab results: Bilirubin level may be raised by nicotinic acid and lowered by phenobarbital.
- Disorders that may alter lab results: Bilirubin levels increase during fasting and may increase during a febrile illness.
Follow-Up Tests & Special Considerations
If history, physical exam, and laboratory tests are normal, see the patient on two to three further occasions during the ensuing 12 to 18 months. If the patient develops no symptoms, reticulocytosis, or new liver function abnormalities, make the diagnosis of Gilbert disease.
Diagnostic Procedures/Other
ALERT
A liver biopsy is not usually needed to exclude other diagnoses (4).
- Some clinicians recommend confirming the diagnosis by reducing daily caloric intake to 400 kcal for 48 hours, which results in a 2- to 3-fold increase in unconjugated bilirubin, but other clinicians consider this impractical and nonspecific for Gilbert disease.
- After 12 hours of fasting, an increase of total bilirubin to >1.9 mg/dL 2 hours after an oral dose of rifampin 900 mg distinguishes patients with Gilbert disease with a sensitivity of 100% and a specificity of 100% (7).
TREATMENT
- Outpatient
- The most important treatment is to make a positive diagnosis of Gilbert disease to reassure the patient and prevent further unnecessary procedures.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
If history, physical exam, and laboratory tests are normal, see the patient on two to three further occasions during the ensuing 12 to 18 months. If the patient develops no symptoms, reticulocytosis, or new liver function abnormalities, make the diagnosis of Gilbert disease.
PATIENT EDUCATION
Reassure the patient that the condition is benign with no known sequelae.
PROGNOSIS
- The disorder is benign with an excellent prognosis.
- There is some preliminary evidence that patients with Gilbert disease may have a lower incidence of cardiovascular disease (8,9). Elevated levels of bilirubin may exert an antioxidation effect (9).
- Patients with Gilbert syndrome are able to serve as donors for right lobe of liver for transplantation (10).
COMPLICATIONS
No known complications
REFERENCES
11 Bosma PJ. Inherited disorders of bilirubin metabolism. J Hepatol. 2003;38(1):107-117.22 Fretzayas A, Moustaki M, Liapi O, et al. Gilbert syndrome. Eur J Pediatr. 2012;171(1):11-15.33 Strassburg CP. Pharmacogenetics of Gilbert's syndrome. Pharmacogenomics. 2008;9(6):703-715.44 Radu P, Atsmon J. Gilbert's syndrome-clinical and pharmacological implications. Isr Med Assoc J. 2001;3(8):593-598.55 Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995;333(18):1171-1175.66 Claridge LC, Armstrong MJ, Booth C, et al. Gilbert's syndrome. BMJ. 2011;342:d2293.77 Murthy GD, Byron D, Shoemaker D, et al. The utility of rifampin in diagnosing Gilbert's syndrome. Am J Gastroenterol. 2001;96(4):1150-1154.88 Inoguchi T, Sasaki S, Kobayashi K, et al. Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. JAMA. 2007;298(12):1398-1400.99 Bulmer AC, Blanchfield JT, Toth I, et al. Improved resistance to serum oxidation in Gilbert's syndrome: a mechanism for cardiovascular protection. Atherosclerosis. 2008;199(2):390-396.1010 Demirbas T, Piskin T, Dayangac M, et al. Right-lobe liver transplant from donors with Gilbert syndrome. Exp Clin Transplant. 2012;10(1):39-42.
CODES
ICD10
- E80.4 Gilbert syndrome
- E80.6 Other disorders of bilirubin metabolism
ICD9
277.4 Disorders of bilirubin excretion
SNOMED
- 27503000 Gilbert's syndrome (disorder)
- 5655007 Inherited disorder of bilirubin metabolism
CLINICAL PEARLS
- Gilbert disease: a mild chronic or intermittent unconjugated hyperbilirubinemia (not due to hemolysis) with otherwise normal liver function
- The hyperbilirubinemia results from impaired hepatic bilirubin clearance (30% of normal). Hepatic bilirubin conjugation (glucuronidation) is reduced, although this is likely not the only defect.
- The most important reason to make the diagnosis of Gilbert disease is to reassure the patient that this is a benign condition with no known sequelae and to prevent unnecessary procedures.
- To diagnose Gilbert disease: History, physical exam, and laboratory tests (LFTs, reticulocytosis, etc.) are normal on visits every 6 months over 18 months.
- A liver biopsy is not usually needed to rule out other liver diseases. The diagnosis can be confirmed by otherwise normal LFTs, no evidence of hemolysis, and the response to fasting or a dose of rifampin.
- The etiology of Gilbert disease can result when the patient has a gene defect resulting in reduced conjugation of bilirubin. The gene defect is necessary but not sufficient to produce Gilbert disease.