Gilbert Disease

Published on 21/04/2017 by admin

Filed under Pathology

Last modified 22/04/2025

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Cytoplasmic Pigment
H&E at high power shows lipofuscin pigment image in centrizonal hepatocytes.

image
PAS-D Stain
Periodic acid-Schiff with diastase digestion accentuates the granular pigment in centrizonal hepatocytes image, even though the pigment is not PAS-D positive.
image
Fontana-Masson Stain
Fontana-Masson stain highlights the increased lipofuscin marked by black staining in the centrizonal hepatocytes.
image
Iron Stain
Prussian blue stain for iron is negative and helps to confirm that the cytoplasmic pigment is not hemosiderin.

TERMINOLOGY

Definitions

• Inherited unconjugated hyperbilirubinemia due to mutations of bilirubin uridine diphosphate glucuronosyltransferase (B-UGT or UGT1A1 ) gene

ETIOLOGY/PATHOGENESIS

Genetic Disorder

• Extra TA in TATAA box of UGT1A1 promoter (this variant is known as B-UGT*28)

image Decreased transcription of gene to 20% of normal
– Decreased conjugation of bilirubin with glucuronic acid
– Decreased conjugation of some drugs (irinotecan, atazanavir, TAS-103, indinavir, tolbutamide, rifamycin)
• Affected patients typically have 2nd condition causing increased bilirubin load

image Examples of additional condition include reduced red blood cell lifespan or impaired hepatic bilirubin uptake

CLINICAL ISSUES

Epidemiology

• Incidence

image Among Caucasians, mutation has frequency of 35-40%
– 11-16% of population homozygous
• Age

image Often diagnosed at puberty, possibly related to increased hemoglobin turnover and inhibition of bilirubin glucuronidation by endogenous steroid hormones
• Sex

image Males affected more than females, possible due to higher rate of bilirubin production in males

Presentation

• Mild unconjugated nonhemolytic hyperbilirubinemia, usually fluctuating and < 3 mg/dL

• Higher bilirubin can occur during illness, stress, or menstrual period
• Otherwise normal liver function
• Jaundice is only finding on physical examination
• Associated with prolonged neonatal jaundice and development of gallstones in patients with hereditary spherocytosis
• Associated with increased risk of toxicity from drugs metabolized by B-UGT
image Irinotecan has been associated with severe diarrhea and neutropenia
image Increased risk of hyperbilirubinemia with atazanavir

Laboratory Tests

• Mild unconjugated hyperbilirubinemia
• Normal alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase
• Increased proportion of bilirubin monoglucuronide in bile
• Rifampin administration causes disproportionate unconjugated hyperbilirubinemia relative to normal patients
• Caloric restriction causes disproportionate unconjugated hyperbilirubinemia relative to normal patients

Treatment

• No treatment necessary

Prognosis

• Excellent

MACROSCOPIC

General Features

• No macroscopic findings

MICROSCOPIC

Histologic Features

• Increased lipofuscin in centrizonal hepatocytes

Predominant Pattern/Injury Type

• Pigment accumulation

Predominant Cell/Compartment Type

• Hepatocyte

DIFFERENTIAL DIAGNOSIS

Lipofuscin Deposition

• Increased lipofuscin can be seen in advancing age, chronic drug ingestion, and as variant of normal

Dubin-Johnson Syndrome

• Pigment is considerably more coarse

Crigler-Najjar, Types 1 and 2

• Severe unconjugated hyperbilirubinemia characterized by total or near-total absence of B-UGT activity
• Mutations in exons 1-5 of UGT1A1 gene
• Biopsy can show cholestasis or appear normal

DIAGNOSTIC CHECKLIST

Clinically Relevant Pathologic Features

• Does not lead to liver inflammation, fibrosis, cirrhosis, or liver failure
• Testing for B-UGT*28 often done to identify patients at risk for certain drug toxicities and to tailor dose

Pathologic Interpretation Pearls

• Increased lipofuscin in centrizonal hepatocytes

SELECTED REFERENCES

1.Ehmer, U, et al. Rapid allelic discrimination by TaqMan PCR for the detection of the Gilbert’s syndrome marker UGT1A1*28. J Mol Diagn. 2008; 10(6):549–552.

2.Costa, E. Hematologically important mutations: bilirubin UDP-glucuronosyltransferase gene mutations in Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis. 2006; 36(1):77–80.

3.Hallal, H, et al. A shortened, 2-hour rifampin test: a useful tool in Gilbert’s syndrome. Gastroenterol Hepatol. 2006; 29(2):63–65.

4.Erdil, A, et al. Rifampicin test in the diagnosis of Gilbert’s syndrome. Int J Clin Pract. 2001; 55(2):81–83.

5.Ishihara, T, et al. Role of UGT1A1 mutation in fasting hyperbilirubinemia. J Gastroenterol Hepatol. 2001; 16(6):678–682.

6.Kadakol, A, et al. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum Mutat. 2000; 16(4):297–306.

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Dubin-Johnson Syndrome Glycogenic Hepatopathy Nodular Regenerative Hyperplasia Eosinophilic Cholecystitis Gaucher Disease Hepatitis B