Материал: Advanced Imaging of the Abdomen - Jovitas Skucas

GALLBLADDER AND BILE DUCTS

extrahepatic biliary activity is identified, biliary atresia can be excluded with a sensitivity approaching 100%. Technetium-99m-DISIDA achieves a high sensitivity but a low specificity. Because of the low specificity, without intestinal activity this study should be considered inconclusive and both neonatal hepatitis and intrahepatic cholestasis are still in the differential diagnosis. In a review of consecutive infants from the Hospital for Sick Children in Toronto, hepatobiliary scintigraphy failed to detect biliary flow into the intestine in 62% (9); of these, 75% were shown to have extrahepatic biliary atresia, 15% neonatal hepatitis, 8% intrahepatic bile duct paucity, and 2% total parenteral nutrition-associated cholestasis. Even total parenteral nutrition-associated cholestasis is in the differential with lack of extrahepatic biliary activity. Poor versus good hepatocyte clearance cannot identify neonatal hepatitis.

Phenobarbital stimulates hepatic microsomal activity. Premedication with phenobarbital prior to scintigraphy increases the accuracy in differentiating between neonatal hepatitis and biliary atresia. Phenobarbital stimulation may not be needed when Tc-99m-BrIDA is used because this tracer undergoes greater hepatic extraction and excretion than Tc-99m-DISIDA or HIDA. Occasionally repeat scintigraphy after administering ursodeoxycholic acid changes Tc- 99m-BrIDA nonexcretors with hepatitis into excretors.

An ERCP is useful in visualizing the extrahepatic bile ducts in suspected neonatal cholestasis but is technically difficult and in most centers is infrequently performed.

Therapy

In neonates and infants with biliary atresia, an intraoperative cholangiogram is usually performed to define the biliary anatomy and determine whether a primary anastomosis is feasible. In a minority the obstruction is at the common bile duct level. Even with intact main right and left hepatic ducts, quite often a Roux-en-Y hepaticojejunostomy is performed. In the absence of cholangiographically visible ducts a hepaticoportoenterostomy (Kasai procedure) is preferred.

Not all infants develop satisfactory biliary drainage following the Kasai procedure, with

Figure 8.3. Percutaneous cholangiogram in a 17–year-old with jaundice reveals numerous cavities communicating with irregular bile ducts. He had biliary atresia as a newborn and underwent a Kasai procedure.

the success rate decreasing with age. Evidence suggests that a low hepatocellular scintigraphic extraction fraction in newborns with biliary atresia is associated with a poor postoperative prognosis (10). Incomplete drainage leads to fibrosis and eventual biliary cirrhosis and the need for liver transplantation (Fig. 8.3).

Hepatobiliary scintigraphy post–Kasai procedure confirms a successful anastomosis by identifying biliary drainage into the intestine.

Of Japanese patients with biliary atresia who underwent a Kasai procedure, 60% became jaundice-free (11); nevertheless, on a long-term basis portal hypertension developed in 50% of anicteric survivors, manifesting as esophageal varices or thrombocytopenia.

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 DubinJohnson syndrome. From an imaging viewpoint these conditions are mostly curiosities, but are included because they are in the differential diagnosis of a jaundiced child.

ADVANCED IMAGING OF THE ABDOMEN

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.

GALLBLADDER AND BILE DUCTS

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 gall-

bladder and bile duct activity but an intense and prolonged liver blush. Scintigraphy thus aids in differentiating Rotor’s syndrome from DubinJohnson 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 auto- somal-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 (12). 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 (13): 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 (14). 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, intraand 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.

Cystic Fibrosis

The liver margin becomes irregular in cystic fibrosis patients. Postcontrast CT reveals inhomogeneous enhancement throughout the liver.

Biliary drainage is deranged in cystic fibrosis, probably due to inspissated secretions.An intrahepatic cholestasis is evident. A typical pattern is dilation of intrahepatic bile ducts, more prominent on the left, a narrowed distal common bile duct, gallbladder dysfunction, and decreased bowel transit. The bile ducts tend toward an irregular, beaded appearance; superficially the appearance can resemble sclerosing cholangitis. These patients are prone to developing gallstones.

A minority of cystic fibrosis children have abnormal liver US, with changes ranging from a diffuse hypoechoic liver with prominent portal tracks, cirrhosis, to portal hypertension (15). Portal track findings tend to be better identified with US than CT (16).

Some patients have prolonged radiotracer retention in intrahepatic ducts even with little or no biochemical evidence of liver involvement. Gallbladder nonvisualization during hepatobiliary scintigraphy in these patients has been attributed to cystic duct obstruction by viscid secretions, although a small, contracted

gallbladder is common and may account for nonvisualization even in the absence of cholecystitis.

Choledochal Cyst

Clinical

The etiology of choledochal cysts is unknown. They are usually classified under congenital cystic biliary malformations, although neonatal viral infection or a bile duct wall abnormality may be responsible. In neonates and infants some authors label this condition simply as congenital biliary dilation. The borderline between a prominent but still normal caliber duct and a choledochal cyst is a matter of definition.

A number of Western authors have commented on the rarity of choledochal cysts in their practices. These cysts are encountered more often in Asia, and most larger studies are from Asia.

A relationship between choledochal cysts and congenital hepatic fibrosis has been speculated; some neonates with choledochal cysts also have periportal fibrosis. An inconsistent association exists between a choledochal cyst and intestinal malrotation. In some adults differentiation between primary chronic dilation leading to bile stasis and stone formation and secondary dilation due to biliary stones and resultant inflammation is not possible.

In 1959,Alonso-Lej et al. (17) classified choledochal cysts into three types: I,fusiform dilation of a portion or entire extrahepatic bile duct system; II, saccular diverticular-like outpouching in extrahepatic ducts; and III, focal dilation of distal common bile duct segment (or common pancreatobiliary channel) within the wall of the duodenum. Type III is also called a choledochocele. Todani et al. (18) expanded this system in 1977 to better reflect a surgical approach. The Todani modification subdivides type I cysts into Ia, aneurysmal dilation; Ib, segmental dilation; and Ic, diffuse, cylindrical dilation; and also includes type IV cysts: IVa, multiple intraand extrahepatic duct cysts; and IVb, multiple extrahepatic cysts only. Also added was a type V: single or multiple intrahepatic duct cysts.

The most common type of choledochal cyst is type I (Fig. 8.4). These cysts tend to be associated with biliary or sphincter of Oddi anom-

Figure 8.4. Type I choledochal cyst involving hepatic duct (arrow). (Courtesy of David Waldman, M.D., University of Rochester.)

alies, and in these individuals reflux of pancreatic content with secondary bile duct wall inflammation and thinning appears to be a reasonable etiology for choledochal cyst formation.

A type II choledochal cyst is a rare congenital malformation. An occasional one presents as an adjacent tumor without an obvious bile duct communication; biliary communication presumably is obliterated due to inflammation.

No strict criteria define a type III cyst (choledochocele), and some authors include dilation of a common channel as a type of choledochocele. Using a strict definition, however, a choledochocele is probably as rare as a type II cyst. These patients are prone to choledocholithiasis. Smaller choledochoceles tend to be asymptomatic.

Among adults with choledochal cysts treated in 17 institutions of the French Associations for Surgical Research, 50% had both extraand intrahepatic bile duct dilation and thus a Todani type IVa choledochal cyst (19); of these, nine included segmental, left lobe duct involvement, and these patients required a combined left lobectomy and extrahepatic cyst excision.

GALLBLADDER AND BILE DUCTS

Biliary carcinoma was present in 12% of these patients.

Some authors label type V dilation of small intrahepatic radicals, as Caroli’s disease (discussed later). Whether Caroli’s disease is indeed a type of choledochal cyst is debatable.

Acquired dilated ducts due to prior stone disease or infection are not considered to be choledochal cysts. Even then, not all dilated ducts fit the above classification. Is a focally dilated cystic duct a choledochal cyst?

These cysts are a cause of prolonged neonatal jaundice. Others are detected in children. Only a rare choledochal cyst manifests during pregnancy. In some adults pancreatitis is their initial presentation. Their propensity to harbor a carcinoma needs to be considered when planning therapy.

The risk of biliary malignancy in a setting of a choledochal cyst increases with age, although cancers have developed in young patients. Bile stasis, irritation, possible mutagenicity of bile mixing with pancreatic secretions, and epithelial damage probably play a role in cancer development. Most tumors are adenocarcinomas but an occasional undifferentiated carcinoma, squamous cell carcinoma, or even adenoacanthoma is encountered. Gallbladder carcinomas have also been reported.

Imaging

In neonates and children, US reveals a choledochal cyst as a cystic structure in the region of the bile ducts. These dilated ducts often extend intrahepatically. The gallbladder ranges from normal in size to somewhat distended.

Traditionally, ERCP has been used to detect and evaluate choledochal cysts in adults, but CT, US, MRI, or scintigraphy is a viable alternative. Imaging reveals a fluid-filled cystic structure. Both CT cholangiography and MRCP detect choledochal cysts with roughly similar image quality and provide information comparable to ERCP; CT cholangiography appears superior to MRCP in detecting any superimposed stones, but the latter also provides information about any associated anomalous pancreaticobiliary duct junction (20) and does not require use a contrast agent. Currently, MRCP is the procedure of choice in evaluating these cysts.

A choledochocele (type III cyst) should be readily detected with MRCP or ERCP; the papilla of Vater bulges, suggesting a submucosal tumor (Fig. 8.5). Their cystic nature is also apparent by endoscopic US.

A carcinoma developing in a choledochal cyst is difficult to detect with imaging; at times a subtle focal or diffuse bile duct wall thickening suggests the diagnosis. These tumors enhance during arterial-phase CT, becoming isodense on delayed phases. Cholangiography reveals either an elevated, irregular outline, or a focal narrowing.

Hepatobiliary cholescintigraphy in patients with choledochal cysts reveals about two thirds of gallbladders nonvisualizing; resected gallbladders in some of these patients do not show evidence of cholecystitis. The diagnostic accuracy of cholescintigraphy for cholecystitis is low in patients with a choledochal cyst. With partial obstruction, scintigraphy shows tracer activity within the cyst; in general, a choledochal cyst tends to fill with radiotracer later than expected and stays filled longer. Radionuclide accumulation in the cyst but no intestinal activity is a not uncommon finding.

Therapy

No curative therapy is possible with extensive intrahepatic involvement of both lobes, aside from liver transplantation.

Figure 8.5. Choledochocele in an 85–year-old man. Contrastenhanced computed tomography (CT) reveals a dilated distal common bile duct indenting the descending duodenum (arrow). More superior images identified a dilated gallbladder. Surprisingly, the patient was not jaundiced. (Courtesy of Patrick Fultz, M.D., University of Rochester.)