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Fatty Liver
Hepatic steatosis occurs in approximately 30% of patients with CF (72) and may be found at any age (19). The pathogenesis of fatty liver remains unclear; malabsorption, dietary deficiencies, primary hepatic dysfunction, and medications have been implicated (1,19,25,72,82,96). Fatty liver is often asymptomatic. In cases of severe steatosis, the liver may become massively enlarged and palpable below the costal margin (19).
Hepatic steatosis may be suggested when abdominal or chest radiographs demonstrate an enlarged lucent liver (Figure 17) (97). Sonographic findings include increased parenchymal echo-genicity with diminished through-transmission, fine echotexture, and poor visualization of the portal triads (Figure 17) (98). Patchy or geometric areas of increased echogenicity may be evident. A relatively hypoechoic "mass" surrounded by echogenic parenchyma is evidence of focal sparing and is distinguished from neoplasm by the absence of mass effect (25). CT shows hepatomegaly with diffuse or multifocal hypoattenuation of the hepatic parenchyma and accentuation of vascular structures (99). Results of sulfur colloid scintigraphy in steatosis are normal because of normal numbers of Kupffer cells.
Cirrhosis and Portal Hypertension
A unique lesion, focal biliary cirrhosis, develops in up to 40% of patients with CF (100,101). The precise pathogenesis of focal biliary cirrhosis remains unclear. Historically, the lesion has been attributed to the accumulation of thickened secretions within the intrahepatic bile ducts (Figure 18), producing periductal inflammation, focal biliary fibrosis, ductular proliferation, and, in 5%-12% of cases, multinodular cirrhosis. Recent studies have examined the role of extrahepatic bile duct stenosis (102,103,104), possible bile toxins (96), and essential fatty acid deficiencies (82). Approximately 1% of CF patients with biliary cirrhosis progress clinically to portal hypertension and end-stage liver disease (1). It remains unclear why 60% of patients with CF do not develop liver disease.
Clinical manifestations of liver disease may occur in CF patients at any age, but the probability of disease increases with age until adolescence (19,101). A familial tendency for the development of cirrhosis has been suggested (72). The relationship, if any, between the severity of pulmonary and hepatic disease in CF patients remains unresolved. In one study, patients with liver disease had substantially less severe bronchopulmonary disease, a finding that was attributed to varying phenotypic expressions of CF gene mutations (103). Other investigators found the evolution of pulmonary and hepatic disease to be independent processes (101). Hepatosplenomegaly or a hard, nontender liver with a nodular edge may be palpable. Results of liver function tests may be normal despite radiologic and biopsy evidence of disease (19,72,105). Conversely, liver biopsy results may be normal despite clear laboratory and radiographic evidence of advanced liver disease, because of the patchy distribution of the process.
Sonographic features of focal biliary cirrhosis correlate poorly with liver function test results and include increased periportal echogenicity and diffusely increased hepatic parenchymal echotexture (106,107). When multinodular cirrhosis develops, characteristic sonographic features include coarsened hepatic echotexture, irregular liver margins, shrunken liver, small right lobe with an enlarged caudate lobe, and diminished visibility of intrahepatic vessels. Rarely, isoechoic or slightly hypoechoic regenerating nodules may be demonstrated (98). Sonographic findings in portal hypertension include splenomegaly, portal vein enlargement, portosystemic collateral vessels, increased portal venous flow, reversed (hepatofugal) portal flow, and ascites. Contrast-enhanced CT readily demonstrates abnormalities of hepatic size and contour, splenomegaly, and portosystemic collateral vessels (Figure 11, Figure 19). Hypoattenuating, regenerating nodules are inconstantly visualized.
The characteristic features of cirrhosis on diagnostic images are nonspecific for CF. The differential diagnosis for cirrhosis in children includes biliary atresia, hepatitis, a-1-antitrypsin deficiency, tyrosinemia, hemochromatosis, Wilson disease, and schistosomiasis (108). Medical therapy for CF patients with liver disease includes dietary optimization and ursodeoxycholic acid. It has not been demonstrated with certainty that any particular therapeutic regimen prevents progression of disease (72,82). In the setting of chronic liver disease and evidence of common bile duct stricture, symptomatic relief of recurrent abdominal pain has been obtained with cholecystojejunostomy or choledochojejunostomy (102). When portal hypertension develops, partial splenectomy, shunt placement, or sclerotherapy may be indicated (19,72,82,101). Most recently, shunting has been performed by placement of transjugular intrahepatic portosystemic stents (13). In severe cases, single (liver) or triple (heart, lung, and liver) transplantations have been performed.
Abnormalities of the Biliary Tree
The gallbladder and cystic duct are affected in 5%-33% of CF patients (19,85,91,107). Abnormalities include cholelithiasis, gallbladder atony, microgallbladder, sludge, thickened trabeculated gallbladder wall, subepithelial cysts, and atrophy or obstruction of the cystic duct. Gallstones (most commonly cholesterol stones) occur in 12%-24% of patients, depending on patient selection criteria (72,82,109). Symptoms of gallbladder disease are less frequent. In one study, only 3.6% of 670 patients developed symptomatic gallbladder disease over a 25-year period (109).
The pathogenesis of gallstone development in CF patients has not been completely elucidated. Pancreatic insufficiency is known to result in elevated fecal bile acid excretion, producing thick lithogenic bile (110,111). Other factors probably play a role in gallstone production, since patients with pancreatic insufficiency and fecal bile salt loss unrelated to CF do not display a marked increase in cholelithiasis (112). Atresia or stenosis of the cystic duct may result from inspissated mucus or mucosal hyperplasia and lead to gallbladder atrophy (91). At autopsy, approximately 25% of gallbladders are true microgallbladders, containing gelatinous material or inspissated mucus (72,113).
Clinical features include recurrent right upper quadrant pain, gastrointestinal upset, food intolerance, fever, and chills. Symptoms are often intermittent and may be confused with other abdominal manifestations of CF such as distal intestinal obstruction syndrome, thus delaying diagnosis. Occasionally, cholelithiasis may be the presenting feature of CF (109).
Although radiographic studies of the gallbladder are abnormal in up to 40% of patients with CF, this frequency rises to 60% in the 15-20 year old age group (72,107). Sonography readily demonstrates gallbladder sludge, cholelithiasis, or microgallbladder (Figure 20). When gallstones are visualized in conjunction with a sonographic Murphy sign, US has a positive predictive value for acute cholecystitis of 92%. Other findings of acute cholecystitis include gallbladder wall thickening and pericholecystic fluid, but it is useful to recall that cholecystitis is an uncommon cause of gallbladder wall thickening in the pediatric population (108). Hypoalbuminemia, ascites, hepatitis, and hepatic venous obstruction should be considered in the differential diagnosis of gallbladder wall thickening when gallstones are not present. Nonvisualization of the gallbladder at hepatobiliary scintigraphy does not necessarily represent acute cholecystitis. Other causes include noninflammatory cystic duct obstruction by tenacious secretions or atrophy with resultant microgallbladder. CT has no routine role in the evaluation of the gallbladder in children but may prove useful in cases complicated by abscess.
Delayed uptake and diminished clearance of technetium-99m disofenin from the liver and biliary tree at scintigraphy has been described in CF patients with liver disease. In two large series, hepatobiliary scintigraphy commonly demonstrated extrahepatic retention of radiotracer, suggestive of distal common bile duct obstruction. In one study, a stricture of the distal common bile duct was identified cholangiographically in the majority of cases (102). In the other, beading and stricturing of the intrahepatic bile ducts were commonly found at endoscopic retrograde cholangiopancreatography, but no abnormality of the extrahepatic duct was present (103). It was proposed that biliary hypomotility, adherence of radiotracer to abnormally viscous mucus, or both contributed to the false-positive obstructive pattern on Tc-99m disofenin scans.
Routine screening of the gallbladder has been suggested for asymptomatic patients with CF. No therapy is advised when the gallbladder is inapparent and no gallstones are present. Management of cholelithiasis in the asymptomatic patient is based on the child's general condition, the probability of developing cholecystitis, and the risks of surgery (72,114). In symptomatic patients with gallstones, cholecystec- tomy is generally recommended (72). In most series, cholecystectomy was performed with relative safety when the patient's medical status was optimized before surgery (109,114).
Hepatobiliary Abnormalities