Familial Hyperbilirubinemias

Alagille’s Syndrome Alagille’s syndrome, or arteriohepatic dysplasia, is an autosomal-dominant multisystemic disorder with nearly complete penetrance and variable expression caused by a genetic defect in the short arm of chromosome 20; it results in mutations to the Jagged 1 (JAG1) protein, a ligand involved in early cell embryogenesis. A wide spectrum of JAG1 mutations includes gene deletions in a minority while most have protein truncating, splicing, and missense mutations
across the gene coding region. This multisystem anomaly leads to atypical facies, pulmonary artery stenosis, butterfly-like vertebral bodies, various cardiovascular anomalies, renal cysts, and growth and mental retardation. The primary liver abnormality consists of a paucity of intrahepatic bile ducts,with the severity varying depending on the specific JAG1 abnormality, and the resultant cholestasis manifests as neonatal jaundice. Liver biopsy tends to detect a
paucity of intrahepatic bile ducts (ductopenia).
Alagille’s syndrome should be suspected in children with unexplained cholestasis and is confirmed by genetic analysis for mutations of the JAG1 gene. Some of these infants progress to cirrhosis, even during childhood. Hepatocellular carcinomas have developed even in pediatric ages. Abdominal imaging in some simply reveals hepatomegaly. The most common abnormality is a liver contour abnormality consisting of either the liver or a lobe having a spherical shape; a sulfur colloid liver–spleen radionuclide scan often shows prolonged excretion. The US findings are similar to those seen with biliary atresia.
Hepatobiliary scintigraphy in a child with Alagille’s syndrome reveals hepatobiliary dysfunction, at times with foci of increased uptake due to compensatory hyperplasia in a setting of cirrhosis. Liver transplantation is the therapy of choice in end-stage liver disease. Incidentally, the growth failure often seen in Alagille’s syndrome patients is not corrected by orthotopic liver transplantation.
Familial Hyperbilirubinemias Traditionally grouped under familial hyperbilirubinemias are nonhemolytic conditions characterized by hepatic dysfunction without gross evidence of hepatocellular injury or biliary atresia. They are subdivided into unconjugated hyperbilirubinemias consisting of Crigler-Najjar syndrome I and II and Gilbert’s syndrome and conjugated hyperbilirubinemias consisting of Rotor’s syndrome and Dubin- Johnson syndrome. From an imaging viewpoint these conditions are mostly curiosities, but are included because they are in the differential diagnosis of a jaundiced child.
Crigler-Najjar Syndrome Crigler-Najjar syndrome is a rare genetic disorder inherited as autosomal dominant with variable penetrance and as an autosomal-recessive trait. It typically manifests in the pediatric age group. This syndrome is due to a gene defect encoding bilirubin uridine diphosphate glucuronosyltransferase (UGT), which is involved in bilirubin conjugation with glucuronic acid. A number of mutations affect the coding region of this gene and lead to a decreased ability to glucuronidate bilirubin. The end result is an increase in unconjugated serum bilirubin level. Patients with this syndrome are homozygous for this defect, resulting in an abnormal form of transferase enzyme. This syndrome is subdivided into types I and II. In type I, the absence of hepatic bilirubin glucuronyl transferase activity results in a severe unconjugated hyperbilirubinemia that invariably is fatal. In type II, a single base pair mutation results in decreased enzyme activity; in
these patients this enzyme responds to phenobarbital therapy, and clinical manifestations are milder and appear similar to those found in Gilbert’s syndrome.
Gilbert’s Syndrome
Gilbert’s syndrome, previously also known as Meulengracht disease in some countries, was redefined in the 1980s and today this term is applied to a chronic unconjugated hyperbilirubinemia due to increased bilirubin turnover. Using such a broad definition, this is a relatively common condition and often manifests as mild hyperbilirubinemia but no clinical illness. It is often diagnosed after puberty. Similar to the Crigler-Najjar syndrome, a deficiency of the bilirubin uridine diphosphate (UDP)-glucuronosyltransferase gene also exists in Gilbert’s syndrome. Several mutations of UGT cause mild reduction of UGT activity and mild hyperbilirubinemia. Patients with both Crigler-Najjar syndrome and Gilbert’s syndrome have been described. Gilbert’s syndrome patients are at increased risk for gallstones. An association with hypertrophic pyloric stenosis has been suggested. Occasionally Gilbert’s syndrome manifests first as postoperative jaundice.
Rotor’s Syndrome
Cholescintigraphy does not visualize the liver, in Rotor’s syndrome patients although they have persistent visualization of the cardiac blood pool and show renal excretion.
Dubin-Johnson Syndrome
Secretion of various conjugates across canalicular and other membranes is mediated by multidrug resistance protein (MRP) pumps; a defect in the MRP2 gene, which encodes MRP2 glycoprotein in the canalicular bilirubin conjugate export pump, leads to a block in excretion of conjugated bilirubin.As a result, a conjugated hyperbilirubinemia develops but no cholestasis is evident. Histology reveals brown pigments consisting of a lipofuscin-melanin complex, mostly in centrilobular zone hepatocytes. At times CT identifies a hyperdense liver. Cholescintigraphy reveals poor-to-no gallbladder and bile duct activity but an intense and prolonged liver blush. Scintigraphy thus aids in differentiating Rotor’s syndrome from Dubin- Johnson syndrome.
Progressive Familial Intrahepatic Cholestasis (Byler Disease) Whether to list this condition under familial hyperbilirubinemia is a matter of definition. Undoubtedly some patients previously included under the hyperbilirubinemia conditions discussed above should be classified under progressive familial intrahepatic cholestasis. Also known as Byler disease, this condition was originally described in an Amish kindred. It is an inherited cholestatic condition having autosomal- recessive inheritance. Rather than one entity, evidence points to a group of similar genetic disorders. The same or very similar conditions exist worldwide; as an example, cholestasis familiaris Groenlandica is a common
recessive disease in East Greenland. Some authors distinguish the condition found in original Amish kindred (Byler disease) from that detected in others (Byler syndrome); the genes responsible appear to be different. Two genetic types are evident: type 1, caused by mutations in the FIC1 gene, coding for P-type adenosine triphosphatases (ATPases); and type 2, due to mutations in the BSEP gene (bile salt export pump), results in defective function of the canalicular bile salt export pump. Others describe three subtypes. In type 1, cholestasis presents in the neonatal period, a severe pruritus develops, histology reveals absence of ductule proliferation, and these children die due to liver failure; an inborn error in primary bile acid secretion has been suggested and a locus mapped to 18q21–q22. In type 2, pruritus does not develop, and an inborn error in primary bile acid synthesis appears to be responsible. Type 3 presents later in life, intra- and extrahepatic bile ducts are patent, often portal hypertension develops with its related complications, and liver failure ensues at a later age; an abnormal
MDR3 gene function appears to be involved. Heterozygosity in these patients appears to be associated with cholestasis of pregnancy. Biliary diversion is often employed in these neonates with cholestasis and pruritus; liver damage is then delayed until orthotopic liver transplantation is available.

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