Liver manifestations of cystic fibrosis

1. Introduction 

Cystic fibrosis (CF) is a genetic disease affecting approximately 1 in 2500 newborns worldwide [1]. Phenotypic expression of CF disease is extremely heterogeneous and may involve sweat glands, pancreas, lungs, liver, intestine, and the Wolffian ducts in male subjects. There is considerable age-related variability, and the severity of disease in specific organs varies considerably within and between patients with CF [2].

Chronic liver disease is one of the major complications of cystic fibrosis. Improved life expectancy and prolonged follow-up have favored better characterization of the hepatic manifestations of CF and allowed direct observation of an increasing number of liver-related events. Its incidence and severity are variable, and diagnosis relies on a combination of clinical evaluation, biochemical testing, and radiological assessment. Identifying patients who have early disease is critical, and the administration of ursodeoxycholic acid appears to be beneficial. The pathogenesis is incompletely understood, and factors that contribute to the variability in incidence and severity are unknown [2].

Liver manifestations complicating the clinical course of the disease have emerged as a significant medical issue. Because it appeared much less frequently than pulmonary and pancreatic disease, liver involvement in CF received little attention for many years. However, it is now considered as the third cause of death after cardio-respiratory and transplantation complications, accounting for approximately 2% of overall CF mortality [3]. Studies showed that liver disease is a relatively early complication of CF, which may be susceptible to prophylactic strategies provided a set of factors are identified to select patients at higher risk for its development [4]. The prevalence studies suggest that clinically obvious CF liver disease usually develops at or before puberty, has a prevalence of 13–17% although isolated hepatomegaly is present in 6–30% of patients and displays a slow progressive course [5]. The incidence drops rapidly after the age of 10 years [6].

These studies also provided evidence that until the most advanced stages are reached, presence of liver disease does not associate a different clinical course of CF in terms of respiratory complications or nutritional problems. Therefore, liver disease should be considered an early complication involving more than one fourth of CF patients, and active follow-up evaluation directed at its detection should be focused at the first decade of life. Studies aimed at preventing CF-associated liver disease should preferentially involve young patients with a history of meconium ileus, male gender, or severe genotype, who are exposed to higher risk for developing this complication [6].

2. Pathophysiology 

The pathognomonic hepatic lesion of CF is focal biliary cirrhosis. The available evidence indicates that this manifestation is the direct expression of the basic defect underlying CF. Focal biliary cirrhosis is currently considered the first example of inherited liver disease resulting from impaired secretory function of the biliary epithelium. It is the most clinically relevant hepatic problem associated with CF, since extension of the initially focal fibrogenic process triggered by chronic biliary damage may lead to multilobular biliary cirrhosis, followed by development of portal hypertension and the related complications. As in other liver diseases characterized by initial involvement of bile ducts and later impairment of hepatocyte function, the hemodynamic consequences of cirrhosis, mainly portal hypertension, are often prominent, whereas liver failure tends to be a late event. This clinical entity has been referred to as the cholestasis/focal biliary cirrhosis/multilobular cirrhosis continuum, and may become the main organ manifestation of CF leading to severe impairment of quality of life and shortened survival of the affected patients [2], [7].

3. Clinical diagnosis and imaging 

No simple and reliable test is available for the diagnosis of liver disease in CF. The most commonly used tests for liver disease are the serum activities of transaminases. However, Lindblad et al. showed in their study that liver biopsies in many patients with only slightly increased serum transaminase levels, i.e., just above reference intervals, showed pathological morphology. Although the diagnostic accuracy is increased by a liver biopsy, this has been questioned in patients with CF owing to the focal character of the liver disease [8].

It is shown that although positive findings on liver biopsy will confirm clinical impressions, normal biopsies unfortunately will not be able to exclude the presence of even advanced disease because of sampling problem [9].

Therefore, imaging modalities are gaining more importance to evaluate the hepatobiliary system in these patients. Among them, real-time ultrasonography (US) is used most extensively to evaluate the hepatobiliary system in these patients. US is considered useful in showing the typical signs of cirrhosis, portal hypertension or extra-hepatic biliary tract abnormalities. Several studies have also described the magnetic resonance (MR) and computed tomography (CT) findings in patients with cystic fibrosis [10], [11].

Advances in all imaging modalities made it possible to reveal the wide spectrum of hepatobiliary disease ranging from asymptomatic gallbladder abnormalities to biliary cirrhosis (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8).

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Fig. 1. US scan of the liver of a 10-year-old CF patient with a normal liver parenchyma.

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Fig. 2. US scan of the liver of a 10-year-old boy with CF in transverse plane shows heterogenously increased liver echogenicity, compatible with fatty liver. His liver function tests are also elevated. No contour irregularity or periportal thickening is identified.

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Fig. 3. US scans of the liver in transverse plane of a 13-year-old CF patient performed in 2003 (a) and 2006 (b). Both images obtained through the same plane reveal distinct progress in the parenchymal disease although his liver function tests were just above normal levels. In the previous exam, liver echogenicity is slightly and heterogeneously increased. No contour irregularity is identified (a). Three years later, contour irregularity of the liver is evident (b).

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Fig. 4. US scan of the liver in sagittal plane of a 9-year-old patient reveals hepatomegaly, and increased liver echogenicity. Periportal thickening is also evident in the distal branches.

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Fig. 5. Longitudinal US scan of the gallbladder of a 5-year-old CF patient shows a contracted and small gallbladder (microgallbladder: marked with calipers) after 9h fasting and in spite of repeated US scans of several days apart (a). Gallbladder measures 6.9mm in size. US scan in transverse plane shows lobulated hyperechogenic areas within the liver which is compatible with pseudomass appearance (b). US scan through the left lobe reveals increased periportal thickness and echogenicity (c). Her AST is slightly above the normal level.

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Fig. 6. Twenty-seven-year-old CF patient with normal liver function tests. US scan of the liver reveals increased periportal thickening around the main portal vein (a). US scan of the left lobe illustrates globular thickening of the left periportal area (b).

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Fig. 7. US (a) and CT (b) scans of the liver of a 7-year-old girl with CF show lobular fatty structures, 1–2cm in size, causing irregular liver contour and heterogeneity in the liver parenchyma. The hyperechogenic areas with hypoechogenic rims on US scans correspond to the hypo attenuated areas on CT scans. The normal liver parenchyma – hypoechogenic on US and hyperattenuating on CT scans – is squeezed in between these peudomasses simulating the rim of a mass.

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Fig. 8. US (a) and CT (b) scans of a 4-year-old patient with CF show the typical but a more diffuse form of pseudomass appearance. The spared (non-fatty) parenchyma of the liver is visualized as hypoechogenic and hyperattenuating rims around fatty areas on US and CT scans, respectively.

Liver can be morphologically normal. As it is described histologically, three types of liver disease were described in CF patients: steatosis, focal biliary fibrosis and multilobular cirrhosis. Fatty infiltration of the liver is the most common hepatic finding on imaging. It was also observed in 30% at biopsy and up to 60% at the autopsy of the CF patients [12], [13]. A partly or completely hyperechoic liver is suggestive of steatosis in ultrasound.

It is likely to reflect malnutrition or deficiency of essential fatty acids, and improvement is seen with enzyme replacement therapy [14].

There is no evidence to suggest that steatosis progresses to cirrhosis and it is accepted as a relatively benign condition [15]. There is also another fatty infiltration pattern that is called pseudomasses, typical for these patients. Pseudomasses can be described as lobulated fatty structures, 1–2cm in size, causing heterogeneity in the liver parenchyma. On US scans they are visualized as hyperechoic areas with hypoechoic rims that corresponded to the low attenuated areas on CT scans. The normal liver parenchyma – hypoechoic on US and relatively hyperattenuating on CT scans – was squeezed in between these fatty areas simulating the rim of a mass. When there is hepatomegaly, contour irregularity and parenchymal heterogeneity, it is consistent with parenchymal disease. Pseudomass pattern may or may not be associated with parenchymal disease [11], [16].

Focal biliary cirrhosis, characterized by focal portal fibrosis and cholestasis, is pathognomonic of CF-related liver disease. It is caused by obstruction of the small intrahepatic biliary ducts which induces ductal proliferation and hyperplasia, and that together with periductal inflammation results in fibrosis. Sonography and MRCP are the best modalities to identify periportal fibrosis. Sonographically peri portal tissues are seen thickened and hyperechoic. In our previous study, we showed that any measurement greater than or equal to 2mm can be considered as increased periportal thickness where as periportal thickness is less than 2mm in the control group [11].

King et al. further evaluated periportal tissue by MR and proposed that periportal thickening was compatible with periportal fat deposition instead of fibrosis. In their study, low-signal-intensity periportal fibrotic tissue was an uncommon finding at MR imaging, being demonstrated in only two patients with cirrhosis and extensive generalized fibrosis. A more common finding at T1-weighted MR imaging was high-signal-intensity periportal tissue, which is suppressed with fat-saturated sequences and indicates fat deposition. This may be explained by findings at pathologic analysis of cells containing fat globules in the fibrotic portal tracts and Ito cells containing large, fat-laden vacuoles in the periportal areas [10].

MR cholangiography (MRC) also demonstrates abnormalities of the intra- or extrahepatic ducts non-invasively. Typical appearances include stricturization, beading, narrowing, or dilatation of the intrahepatic ducts; diffuse narrowing or focal stricturization of the common bile duct; and calculi in the intra- and extrahepatic bile ducts. These findings are similar to sclerosing cholangitis. Caudry et al. found these findings in 40% of their patients and 12% progressed to macronodular cirrhosis [14]. Durieu et al. evaluated adult cystic fibrosis patients with MRC. All patients who had the evidence of liver diseases showed abnormal findings on MRC. On the other hand, half of the patients without any evidence of the clinical, biological or ultrasonographic criteria of liver disease had positive MRC findings. Intrahepatic biliary anomalies were shown in 69% of their patients, very close to the prevalence of biopsy and autopsy studies in adult patients. All the abnormal MRC images showed dilatations of the intrahepatic biliary tract: either isolated dilatation (simple biliary lesion) or PSC-like (with stenosis and rigidity), both corresponding to those seen in cholangitis (Fig. 9) [17].

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Fig. 9. US scan of a 16-year-old patient reveals heterogenous liver parenchyma with periportal thickening and increased echogenicity (a). Although bile ducts are normal in caliber there is focal dilatation and narrowing (bead like appearance) at the left intrahepatic bile ducts (white arrowhead) at MRC (b).

Unlike other studies, none of their patients had obstruction in the common bile duct. Cholelithiasis is common but intrahepatic stones are very rare in adult CF patients [18], [19].

Imaging of the gallbladder often creates difficulty in CF patients. Gallbladder may be normal, too small or may not be seen at all. Gallstones are also a common finding. In literature, gallbladder anomalies were detected in 24–50% of the cases either by US or MRC. Since most patients are asymptomatic, no treatment or investigation is required [20], [21].

Microgallbladders containing gelatinous material or mucus have been described at autopsy in 23% of patients with cystic fibrosis and can result in false-positive results at hepatobiliary scintigraphy [22]. Atresia or stenosis of the cystic duct may result from viscous mucus or mucosal hyperplasia, leading to gallbladder atrophy, although small gallbladders have also been described in patients with a patent cystic duct [10].

4. Conclusion 

Both MR and US imaging are useful and non-invasive techniques for the assessment of hepatobiliary complications and guiding further management in cystic fibrosis. A variety of related hepatic abnormalities can be clearly demonstrated in advance with sonography. It should be the first modality for screening liver disease in these patients. However, assessment of the intra and extrahepatic biliary tree seems to be better with MR cholangiography. Repeat MR examinations can also be performed to evaluate disease progression or response to therapy without radiation exposure, the risks associated with endoscopic retrograde cholangiopancreatography, or the difficulties encountered in comparing findings in serial US examinations performed by different observers. CT is also useful to evaluate the liver parenchyma in patients who developed macronodular cirrhosis and portal hypertension.