Imaging findings in congenital hepatic fibrosis

1. Introduction 

CHF is a developmental malformation that belongs to the family of hepatic ductal plate malformation, which resulted from persistence of excess embryonic bile duct structure in the portal tracts [1]. It is almost always associated with autosomal recessive polycystic kidney disease and since that it is considered a variant of autosomal recessive polycystic kidney disease (ARPKD) with less renal involvement and longer survival [1], [2]. It is histologically defined by fibrous enlargement of periportal tracts and irregularly shaped proliferating bile ducts [1], [2]. There is a progression in the extent of liver fibrosis over time, with occasional evolution into true cirrhosis [3].

The onset of signs and symptoms is variable, ranging from early childhood to the 5th or 6th decade of life, but most cases are diagnosed during adolescence or young adulthood [4]. Although the initial manifestations of the disease are the signs of portal hypertension and related problems [5], the clinical findings are often nonspecific and the diagnosis can be extremely difficult. Traditionally liver biopsy has been the mainstay of the diagnosis of CHF, but recently reported studies have highlighted the importance of imaging in diagnosis of CHF [6], [7].

In this article we reviewed the radiologic literature on CHF and summarized liver findings in patients with CHF.

2. Epidemiology and pathophysiology 

Although autosomal recessive mode of inheritance accepted, up to 56% of cases reported to be sporadic [4]. In most, if not all cases, CHF is associated with renal tubular ectasia, corresponding to ARPKD [2]. Mutations in the polycystic kidney and hepatic disease 1 gene (PKHD1) on chromosome 6p21.1-p12 were recently identified as the genetic cause of autosomal recessive polycystic kidney disease/CHF [8], [9]. This gene is responsible primarily for the expression of the protein named polyductin or fibrocystin and the defect of this protein leads to cyst formations in different organ systems including liver, pancreas and kidney [1].

CHF is a variant of ductal plate malformation, which resulted from a persistence of excess embryonic bile duct structure in the portal tract. A ductal plate is defined as a cylindric layer of cells that surrounds a branch of the portal vein, which develops during the first week of gestation. It is a precursor unit for the set up of the definitive intrahepatic bile ducts of the embryological liver. This temporary structure undergoes a process of remodeling and involution [1]. Biliary anomalies may develop at various stages of this involution-remodeling process, and the timing or stage of development determines the resulting clinicopathologic disorder [10]. This developmental process causes a spectrum of disease including congenital hepatic fibrosis, biliary hamartomas, autosomal dominant polycystic disease, Caroli's disease and choledochal cysts. CHF and bile duct hamartomas are manifestations of ductal plate malformation of the small interlobular bile ducts [2], [5], [11] whereas Caroli's disease is result of ductal plate malformation of the large intrahepatic bile ducts [2]. All these entities related to developmental abnormalities of the ductal plate are collectively named as the fibropolycystic diseases of the liver and can be found in the patients with several different combinations [1]. The histopathological hallmarks of this class of diseases are the varying degrees of persistent bile duct structures, fibrosis and ductal dilatation.

3. Clinical presentation 

The clinical manifestation of congenital hepatic fibrosis is nonspecific, which makes the diagnosis of this disorder extremely difficult. Different forms of CHF have been recognized; portal hypertensive (which is the most common), cholangitic, mixed and latent types [12]. The cholangitic and mixed forms may be due to coexisting Caroli's syndrome, although some authors have reported cases where no macroscopic dilatation of the bile ducts was evident [1].

In most patients, the first manifestations of the disease are signs or symptoms related to portal hypertension, especially splenomegaly and varices, often with spontaneous gastrointestinal bleeding. The precise pathogenesis of development of portal hypertension is unknown, but it has been attributed to the compression of portal vein radicles in the fibrous bands and to an anomaly in the branching pattern of the portal vein, giving rise to hypoplastic and involutive branches [5]. The associated vascular malformations of the liver include abnormalities in the ramification or cavernous transformation of the portal vein and hyperplasia-hypertrophy of the hepatic artery branches in portal tracts [1], [13].

Although most cases are diagnosed during adolescence or young adulthood, the onset of the signs and symptoms is varied from early childhood to the 5th or 6th decade of life [1]. Liver function test results may remain normal or be only modestly elevated [5], [13].

4. Associated disorders 

Among all the associated abnormalities renal disorders are by far the most common concomitant clinical problem, particularly ARPKD. Although the association of ARPKD and CHF is somewhat controversial, there is growing evidence that the two conditions are actually one disorder, the apparent differences being related to the length of survival of the patients and the variable expression of the underlying genetic abnormality [14], [15]. Clinically, the renal disease is predominant in neonates and infants, whereas the liver related problems are more common in older children and adults. CHF may also be associated with autosomal dominant polycystic kidney disease, renal dysplasia, nephronophtisis, and medullary sponge kidney [2], [16].

CHF may also be accompanied by other ductal plate malformations, including biliary cysts, Caroli's disease, von Meyenburg complex and choledochal cyst [1]. Caroli's disease is a congenital dilatation of the larger intrahepatic bile ducts and corresponds to incompletely remodeled ductal plate remnants with a variable degree of dilatation. When this disease is combined with the changes of CHF, the disorder is termed Caroli's syndrome [4]. The clinical manifestations of Caroli's disease with CHF depend on whether ectasia of the intrahepatic ducts or hepatic fibrosis is the predominant lesion. The former may produce clinical manifestations as a result of biliary stone formation, cholangitis, and occasionally liver abscess. In the latter situation, the clinical manifestations are mainly those of portal hypertension and the most significant symptom is hematemesis.

Many other conditions other than renal and biliary lesions, have been reported to be associated with CHF such as pulmonary emphysema, congenital heart disease, pulmonary hypertension with arteriovenous fistula, familial absence of depressor anguli oris, lymphangiectasia, aneurysms of cerebral and renal arteries, and Joubert's syndrome [17], [18], [19], [20], [21], [22].

Although development of cholangiocarcinoma can be seen as a late complication in patients with ‘fibropolycystic’ disease such as Caroli's disease and choledochal cyst, it is rarely reported in patients with CHF [23], [24], [25]. Similarly hepatocellular carcinoma can also develop in patients with CHF [26].

5. Imaging 

Morphological alterations of the liver, which include hypertrophy of the left lateral segment and caudate lobe, normal or hypertrophic left medial segment, atrophic right lobe has been reported as distinct morphologic features of patients with CHF [6]. In contrast to advanced viral and alcoholic cirrhosis, where medial segment of the left lobe undergoes substantial atrophy and reduction in size, this lobe is generally preserved or sometimes gets larger in patients with CHF [6]. An enlarged hepatic artery has been described with associated large multiacinar regenerative nodules as a consequence of augmented arterialization of the liver [2]. These regenerative nodules are better defined as large regenerative nodules due to the presence of fibrosis in the surrounding liver and the potential progression to cirrhosis. Alterations of the parenchymal echotexture and homogeneity may be the key findings for the recognition of the progress to cirrhosis.

The problems regarding the biliary system are the main source of the most of the clinical symptomatology, as mentioned in the pathophysiology. Fibrosis and ductal dilations are among the most prominent findings in the histopathology and both can be easily detected with imaging. Ductal dilations can be clearly seen in all imaging modalities and continuous and non-continuous tubular cystic structures and fibrosis can be seen as periportal thickening.

Kidneys are the second most common affected organ. Parenchymal cysts are the hallmark lesion of the disease process and can be clearly and easily detected with all imaging modalities. US may be particularly useful for the diagnosis and evaluation of the cysts as well as the detection of the alterations of the parenchymal echotexture, indicative of the underlying disease process.

5.1. Ultrasound 

In an appropriate clinical context diagnosis of CHF can be made by US with the help of clinical and morphological findings [7]. The distinctive and suggestive morphological findings (hypertrophy of the left lateral segment and caudate, normal or hypertrophic left medial segment, atrophic right lobe) that are highly characteristic for CHF can be recognized easily with US. Furthermore the assessment of parenchymal echotexture, presence of hepatosplenomegaly and dilatation of the intrahepatic and extrahepatic bile ducts and concomitant focal cystic or solid lesions such as regenerative liver nodules and periportal thickening can be done at the same time (Fig. 1).

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Fig. 1. Two patients with CHF (a) US image shows widespread dilatation of the intrahepatic bile ducts in a 19-year-old male patient (white arrows). Also note the coarse echotexture of the liver parenchyma representing background hepatocellular injury. (b) Parenchymal dysplastic nodules (white arrows) and associated ductal dilations in a different patient.

US is also very useful in Caroli's syndrome revealing the dilated intrahepatic bile ducts and detecting the stones in the ducts. Ultrasound may fail to reveal the connection between cystic structures and bile ducts, if so these structures can be misinterpreted as hepatic cysts, which is the most common feature of ADPKD [27]. Considering the highly prevalent kidney disorders in these patients US can also be highly effective in examining the renal parenchymal and echotexture abnormalities, size, cortical thickness and detection and characterization of the cysts (Fig. 2).

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Fig. 2. Multiple renal medullar cysts representing the associated ARPKD in the left kidney of a 19-year-old patient (white arrows) (same patient as in Fig. 1a).

Color Doppler and spectral analysis may provide highly valuable data about the portal hypertension, which is the main clinical manifestation. Portal and splenic vein dilations, vascular patency, the flow direction in the portal and hepatic veins and collateral vascularization may be easily and quickly examined. Portal vein ramification or cavernous transformation of the portal vein can also be assessed with color Doppler ultrasound.

The role of US may be more important in pediatric age group who will need imaging follow-up for long years and in patients with renal parenchymal problems who are intolerant to intravenously used contrast agents, particularly the iodinated CT contrast agents.

5.2. Computed tomography 

In the past intravenous pyelography and CT has been utilized for the diagnosis of CHF [23]. Although little is known about the radiologic diagnosis of CHF, there are few reports which described some distinct CT features of CHF that may help making a correct diagnosis [6], [28]. Zeitoun et al. retrospectively evaluated 18 patients with CHF and found hypertrophy of the left lateral segment, normal sized or hypertrophic medial segment and atrophic right lobe, varices, splenomegaly, associated ductal plate malformations, and renal abnormalities can be utilized as distinctive features of CHF (Fig. 3) [4]. Periportal cuffing, indicative of fibrotic process, may also be easily detected with CT (Fig. 3a). Commonly accompanying renal disorders of CHF can also be quickly diagnosed. Associated Caroli's disease may also be easily detected with its characteristic segmental and non-continuous ductal dilatation and central dot at the center, representing venous branch at the middle of the dilated duct (Fig. 4).

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Fig. 3. Axial CT images of a 13-year-old patient with periportal fibrosis and signs of portal hypertension (a) characteristic periportal cuffing, believed to represent periportal fibrosis, may clearly be demonstrated with CT (black arrow). Atrophy of the right liver is also noted, (b) perisplenic collaterals (black arrow) at the splenic hilum and splenomegaly are seen, indicators of portal hypertension.

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Fig. 4. CT image of a 14-year-old patient with biopsy proven CHF with associated Caroli's disease. Cystic and non-continuous ductal dilatation with characteristic central dot sign is seen (black arrow).

5.3. MRI and MRCP 

Magnetic resonance cholangiopancreatography (MRCP) techniques usually rely on heavily T2-weighted turbo spin-echo sequences, which display fluid within biliary duct as high signal intensity structures against markedly suppressed signal of background tissue [29], [30]. HASTE is an ultrafast T2-weighted sequence, which allows subsecond slice acquisition. This largely overcomes the problem of motion artifact in MRCP, which can be a problem, particularly, in pediatric patients. HASTE is the current sequence of choice for MRCP, because it essentially eliminates the problem of motion artifact, and its better contrast-to-noise ratio and increased spatial resolution when compared with FSE or gradient-echo based T2-weighted sequences [29].

MRCP seems to be a sensitive method for revealing biliary and renal abnormalities associated with congenital hepatic fibrosis, even when sonography findings are normal (Fig. 5) [7]. MRCP may demonstrate unusual distribution of the biliary three, with mild and more or less uniform dilatation peripherally contrasting with slenderness and poor visibility centrally (Fig. 6). The macroscopic dilatation of the bile ducts generally indicates the presence of associated Caroli's disease (Fig. 7) [4]. With MRCP it is possible to demonstrate communications between the dilated ducts and normal biliary tree especially with projectional images [27].

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Fig. 5. Renal cysts at T2 weighted fat suppressed MR imaging in a 11-year-old female patient (black arrow). Splenomegaly and periportal cuffing may also be easily detected as associated findings.

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Fig. 6. MRCP image, same patient in Fig. 5, demonstrating diffuse periportal fibrosis with diffuse dilation of the of the intrahepatic bile ducts.

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Fig. 7. Axial post contrast T1-weighted image of the same patients in Fig. 5, Fig. 6 demonstrating signs of portal hypertension (black arrow) and Caroli's disease (white arrow).

MR features of portal hypertension are characteristic and can be evaluated in detail with T1 weighted sequences. The fibrous bands are seen as low-signal band of variable width traveling along the portal vessels (Fig. 8). Periportal hepatic fibrosis can be demonstrated in T2 weighted sequences as high signal areas among the portal vessels (Fig. 9). Systemic hypervascularization can be demonstrated on the early post-gadolinium images. Hepatic parenchymal focal lesions, mostly regenerative nodules may also be easily detected with MR and further characterization may be also highly sensitive and specific (Fig. 10). Presence of cholangitis may also be assessed with post-gadolinium T1-weighted images. Another possible advantage of MR is its capability of helping to make the preoperative planning of the affected children in the cholangitic form of the CHF obviating the need of preoperative invasive cholangiogram [7].

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Fig. 8. Axial MR images in two different patients with CHF (a) T1-weighted axial image in a 11-year-old male patient reveal prominent cuffing around the left and right portal vein branches (white arrows). (b) T1-weighted gradient echo fat suppressed image after contrast administration reveals less prominent periportal cuffing (white arrows).

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Fig. 9. In two different patients note (a) periportal cuffing (white arrow) and associated renal cysts (black arrow) on fat suppressed axial T2-weighted imaging. (b) Coronal fast steady state free precession image (trueFISP), note periportal cuffing (black arrows) and perisplenic collaterals (white arrow).

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Fig. 10. Same patient as in Fig. 5. Non-contrast T1-weighted in-phase axial image of the same patient demonstrates the regenerative-dysplastic nodules as hyperintense round lesions (black arrows). No interval change was observed at 2 year follow-up.

6. Which modality? What to use, when? 

Selection of the most appropriate modality is one of the most important aspects of the tasks of the radiologists. Ideally such a modality should be inexpensive, poses no radiation risk to the patient, easy to perform and interpret. Unfortunately, for today, there is no “one fits all” imaging modality.

US is generally regarded as the first line modality used in the diagnostic process with its high utility, lack of radiation exposure, its capability of detecting the bile duct and liver parenchymal abnormality. Particularly its unique capability of detecting the parenchymal heterogeneity and the associated kidney abnormalities also accentuates its role in the diagnosis.

CT is also generally regarded, as the “workhorse” of abdominal imaging. With the development of the multidetector CT technology, it is no longer a single plane imaging modality. Today with the advent of the post-processing softwares, the reconstructions on several planes are possible. It may clearly depict the changes in the gross morphology of the liver, volume measurements and vascular mapping may also be easily made within the patients who are candidates of liver transplantation.

Multiplanar imaging capability and lack of radiation makes MRI more attractive, especially, in pediatric age group. With the implementation of new rapid and high-resolution sequences, like HASTE, MRCP became a routine and widely respected imaging modality for the evaluation of biliary tract. With MRCP, whole biliary ductal system can be thoroughly and highly effectively examined. The other biliary abnormalities like Caroli's disease, biliary cysts and choledochal cysts can also be detected with high certainty [7]. Qualitative determination of the parenchymal fibrosis, the detection of the associated ARPKD must also be stated among the other advantages of MRI.

Definitive diagnosis of CHF is determined on the basis of liver biopsy. Although liver biopsy has high sensitivity for the diagnosis of CHF, it has a low specificity [27]. Its routine use in the diagnosis must be questioned and it may be reserved for the patients with equivocal findings. With today's imaging technology and increased experience in the field it must not be regarded as a highly invasive test and may be easily done when the clinical circumstances dictates no other options rather than the histopathologic diagnosis. But in some patients the clinical circumstances may not permit its realization. It may be dangerous in patients with thrombocytopenia and transjugular biopsy may be preferred over the percutaneous biopsy in the selected cases [31].

In the selection of the right imaging modality, several different factors must be taken into account like the clinical presentation, age of the patient, the radiologist's or the institute's preferences and experience. With today's imaging technology several modalities can be liberally used as complementary studies.

7. Conclusion 

Although the predominant clinical problem is portal hypertension and related disorders in majority of the patients, CHF must be viewed and treated as a multisystem disorder. The familiarity of the radiologists to the imaging findings to this rare medical problem may not only facilitate to reach a correct diagnosis but also may permit the implementation of a dedicated and prompt treatment while obviating the need of liver biopsy.