Conjugated Hyperbilirubinemia

Dubin-Johnson syndrome Autosomal recessive Impaired biliary excretion of bilirubin

glucuronides due to mutation in canalicular

multidrug resistance protein 2 (MRP2)

Pigmented cytoplasmic

globules; ?epinephrine

metabolites

Innocuous

Rotor syndrome Autosomal recessive Decreased hepatic uptake and storage? Normal Innocuous

Decreased biliary excretion?

UGT, uridine diphosphate-glucuronyltransferase.

all patients develop normally, but there is a risk for some neurologic damage from kernicterus.

Gilbert syndrome is a relatively common, benign, somewhat heterogeneous inherited condition presenting with mild, fluctuating hyperbilirubinemia. The primary cause is reduction in

hepatic bilirubin glucuronidating activity to about 30% of normal levels. In most patients, two extra bases (TA) are found in the TATAA element of the 5' promoter region (creating an A

(TA)7 TAA element rather than the normal A(TA)6 TAA, resulting in reduced expression of UGT1A1. Alternatively, patients may be heterozygous for missense mutations in the UGT1A1

gene. Affecting some 6% of the population, the mild hyperbilirubinemia may go undiscovered for years and is not associated with functional derangements. When detected in adolescence

or adult life, it is typically in association with stress, such as an intercurrent illness, strenuous exercise, or fasting. Gilbert syndrome has no clinical consequence except for the anxiety that a

jaundiced sufferer might justifiably experience with this otherwise innocuous condition.

Dubin-Johnson syndrome results from a hereditary defect in hepatocellular excretion of bilirubin glucuronides across the canalicular membrane. The defect is due to absence of the

canalicular protein, the multidrug resistance protein 2 (MRP2; located on chromosome 10q24), that is responsible for transport of bilirubin glucuronides and related organic anions into bile.

[12] The liver is darkly pigmented owing to coarse pigmented granules within the cytoplasm of hepatocytes ( Fig. 18-6 ). Electron microscopy reveals that the pigment is located in

lysosomes, and it appears to be composed of polymers of epinephrine metabolites, not bilirubin pigment. The liver is otherwise normal. Apart from chronic or recurrent jaundice of

fluctuating intensity, most patients are asymptomatic and have a normal life expectancy.

Rotor syndrome is a rare form of asymptomatic conjugated hyperbilirubinemia with multiple defects in hepatocellular uptake and excretion of bilirubin pigments. The liver is not

pigmented. As with Dubin-Johnson syndrome, patients with Rotor syndrome exhibit jaundice but otherwise live normal lives.

Cholestasis

Cholestatic conditions, which result from hepatocellular dysfunction or intrahepatic or extrahepatic biliary obstruction, also may present with jaundice. Alternatively, pruritus is a

presenting symptom, related to the elevation in plasma bile acids and their deposition in peripheral tissues, particularly skin. Skin xanthomas (focal accumulations of cholesterol) sometimes

appear, the result of hyperlipidemia and impaired excretion of cholesterol. A characteristic laboratory finding is elevated serum alkaline phosphatase, an enzyme present in bile duct

epithelium and in the canalicular membrane of hepatocytes that is released into the circulation because of the detergent action of retained bile salts on hepatocyte membranes. An isozyme

derived from posttranscriptional changes is normally present in many other tissues such as bone, so the increased levels must be verified as being hepatic in origin. Another canalicular

ectoenzyme, g-glutamyl transpeptidase, is also released into the circulation. The elevated levels of these

Figure 18-6Dubin-Johnson syndrome, showing abundant pigment inclusions in otherwise normal hepatocytes (H&E).

Figure 18-7Illustration of the morphologic features of cholestasis (right) and comparison with normal liver (left). In the parenchyma (upper panel), cholestatic hepatocytes (1) are enlarged

with dilated canalicular spaces (2). Apoptotic cells (3) may be seen, and Kupffer cells (4) frequently contain regurgitated bile pigments. In the portal tracts of obstructed liver (lower panel),

there is also bile ductular proliferation (5), edema, bile pigment retention (6), and eventually neutrophilic inflammation (not shown). Surrounding hepatocytes (7) are swollen and

undergoing degeneration.

TABLE 18-5-- Inherited Cholestatic Conditions

Common

Date: 2016-04-22; view: 771