| Unconjugated |
| 1-Gilbert's syndrome: |
| autosomal recessive and the most common familial hyperbilirubinaemia and affects 2-7% of the population. It is asymptomatic and is usually detected as an incidental finding of a slightly raised bilirubin (17-102 μmol/L or 1-6 mg/dL) on a routine check. All the other liver biochemistry is normal and no signs of liver disease are seen. There is a family history of jaundice in 5-15% of patients. Hepatic glucuronidation is approximately 30% of normal, resulting in an increased proportion of bilirubin monoglucuronide in bile. Most patients have reduced levels of UDP-glucuronosyl transferase (UGT-1) activity, the enzyme that conjugates bilirubin with glucuronic acid. Mutations occur in the gene (HUG-Br1) encoding this enzyme, with an expanded nucleotide repeat consisting of two extra bases in the upstream 5' promoter element. This abnormality appears to be necessary for the syndrome, but is not in itself sufficient for the phenotypic expression of the syndrome. |
| 2-Crigler-Najjar syndrome: |
| Conjugated |
A 22-year-old female college student is referred to a gastroenterologist for evaluation of painless jaundice . She initially presented to a campus health center for evaluation of a flu-like illness with high fevers, where mild scleral icterus was noted. Initial laboratory studies revealed a normal complete blood count, normal alkaline phosphatase level, and normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels as well as a total serum bilirubin of 3.7 mg/dL (normal 0.8-1.2) and direct serum bilirubin of 0.5 mg/dL (normal 0.5-1.1). Serologic testing for hepatitis was negative. At this visit, the flu-like illness has spontaneously resolved, and repeat laboratory testing reveals that total serum bilirubin has returned to normal. She has not taken any medications for his illness. What is the most likely cause of this patient’s elevated serum bilirubin level?
ReplyDeleteA. Epstein Barr virus
B. Gilbert’s syndrome
C. Alcohol consumption
D. Primary sclerosing cholangitis (PSC)
E. Transient biliary obstruction caused by a gallstone
Explanation
Gilbert’s syndrome is a classic inherited disorder of bilirubin metabolism that presents with an unconjugated hyperbilirubinemia. A mutation in the gene that codes for the uridine diphospho-glucuronate glucuronosyltransferases (UGTs; enzymes that moderate glucuronidation of various compounds including bilirubin) leads to decreased production of bilirubin-UGT, which in turn causes decreased excretion of conjugated bilirubin. In patients with Gilbert’s syndrome, elevated serum bilirubin is typically caused by physical stressors, such as dehydration, febrile illnesses, periods of fasting, extreme physical exertion, and the ingestion of certain drugs. Gilbert’s syndrome is a benign condition that is not associated with progressive jaundice or liver disease. Acute viral hepatitis such as Epstein Barr infection, alcohol consumption, PSC, and transient biliary obstruction would not present with an isolated elevation of serum bilirubin without other abnormal liver function tests.
Which of the following is true of Gilbert's syndrome?
ReplyDelete1-nheritance is usually autosomal dominant Incorrect answer selected
2- Serum conjugated bilirubin levels are elevated
3-Serum bilirubin levels are decreased by fasting
4-Serum bilirubin levels are decreased by liver enzyme inducers
5-There is bilirubinuria
Gilbert's syndrome is typically inherited in an autosomal recessive fashion and affects 2-5% of the population. The mutation in this instance is in the promoter region of the gene and leads to lower enzyme levels, penetrance is incomplete (not all individuals homozygous for the mutation have Gilbert's). A missense mutation in the UDPGT gene can give rise to Gilbert's. In this case inheritance appears to be autosomal dominant. This mutation is substantially less common than that occurring in the promoter region and appears to have been described predominantly in those of Asian descent. In both cases UDP glucuronyl transferase levels are reduced leading to an unconjugated hyperbilirubinaemia.
Whilst serum bilirubin levels are elevated the other LFT's are normal. Jaundice deepens after a period of fasting or intercurrent illness but bilirubin levels are reduced by enzyme inducers such as phenobarbitone.
As unconjugated bilirubin is tightly bound to albumin, it cannot cross the glomerulus and is therefore not found in the urine. This contrasts with the bilirubin-glucuronide-albumin complex formed in patients with cholestatic jaundice (and raised conjugated bilirubin levels) where 1% of the complex is dialysable and although most of the bilirubin is reabsorbed in the proximal tubule some bilirubin is detectable in the urine.
Which of the following concerning the conjugation of bilirubin is correct?
ReplyDelete1-It is catalysed by a glucuronyl transferase
2-It is impaired in Dubin-Johnson syndrome
3-It is increased by valproate
4-It is inhibited by rifampicin
5-It occurs in the Kupfer cells of the liver
In Dubin-Johnson syndrome conjugation is normal, but excretion from the hepatocyte into the bile is impaired, resulting in a conjugated bilirubinaemia.
Sodium valproate is an enzyme inhibitor.
Rifampicin is an enzyme inducer.
Bilirubin is conjugated in the hepatocytes.
In Gilbert's syndrome, bilirubin cannot enter the hepatocyte and unconjugated bilirubinaemia occurs, as it does in Crigler-Najjar syndrome, where bilirubin does not conjugate due to malproduced bilirubin glucuronyl transeferase.