Fibrocystic liver disease refers to a heterogeneous group of disorders with shared, but also distinct, pathophysiologic and clinical features. Cystic dilatation of intrahepatic bile duct structures and variable degrees of portal fibrosis are the hallmarks of fibrocystic liver disease. In many instances, there are morphologic abnormalities in the kidneys that parallel those of the liver. It has been recognized for centuries that hepatic and renal cysts are seen in the same individuals , although it has not always been accepted that they are manifestations of the same diseases. The older literature contains confusing descriptive classifications of fibrocystic diseases, with imprecise and overlapping definitions. Even now, attempts at describing clinical and radiographic features, prognosis, natural history, and treatment are somewhat hampered by reliance on these descriptive reports. However, much of the molecular basis for these disorders has been elucidated, and clinical diagnoses are being modified using more exact genetic criteria. The current consensus is that genetic determinants of differentiation and development of renal tubules and biliary structures result in a broad spectrum of congenital abnormalities grouped under the heading of fibrocystic liver and kidney disease.
Fibrocystic liver disease refers to a heterogeneous group of disorders with shared, but also distinct, pathophysiologic and clinical features. Cystic dilatation of intrahepatic bile duct structures and variable degrees of portal fibrosis are the hallmarks of fibrocystic liver disease. In many instances, there are morphologic abnormalities in the kidneys that parallel those of the liver. It has been recognized for centuries that hepatic and renal cysts are seen in the same individuals , although it has not always been accepted that they are manifestations of the same diseases. The older literature contains confusing descriptive classifications of fibrocystic diseases, with imprecise and overlapping definitions. Even now, attempts at describing clinical and radiographic features, prognosis, natural history, and treatment are somewhat hampered by reliance on these descriptive reports. However, much of the molecular basis for these disorders has been elucidated, and clinical diagnoses are being modified using more exact genetic criteria. The current consensus is that genetic determinants of differentiation and development of renal tubules and biliary structures result in a broad spectrum of congenital abnormalities grouped under the heading of fibrocystic liver and kidney disease. For these reasons, and to appreciate more thoroughly the shared pathogenesis and implications for organogenesis, fibrocystic liver disease and corresponding renal counterparts are discussed together.
Fibrocystic liver disorders are grouped under “ciliopathies,” or defects in primary or non-motile cilia. Primary cilia function as the “sensory antennae” of the cell and extend outward from the cell surface to act as a signal transducer between the extracellular and intracellular spaces. Primary cilia have multiple functions during embryonic development and tissue morphogenesis, with important roles in cholangiocytes and renal tubular epithelium. Thus mutations in the regulatory proteins of these organelles play important roles in the pathogenesis of fibrocystic liver and kidney diseases.
While autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are the most common ciliopathies associated with both liver and kidney disease, variable degrees of renal and/or hepatic involvement occur in many other ciliopathies, including Joubert, Bardet-Biedl, and Meckel-Gruber syndromes. The ductal plate malformation (DPM), a developmental abnormality of the portobiliary system, is the basis of the liver disease in ciliopathies that manifest as congenital hepatic fibrosis (CHF), Caroli syndrome (CS), and polycystic liver disease (PLD).
Embryologic development of the liver has been discussed in Chapter 1 and will not be fully reviewed here. However, to understand this group of developmental disorders, it is necessary to review the stages of formation of the macroscopic and microscopic biliary tree. At about the eighth week of gestation, precursor cells that lie adjacent to the hilar portal vein vessels dramatically increase production of cytokeratin. This sleeve-like layer of cells duplicates and extends toward the periphery along small intrahepatic portal vein branches. The resultant double-layered sleeve of cytokeratin-rich cells that are separated by a slit- or plate-like lumen has been designated as the ductal plate. The ductal plate undergoes progressive remodeling from 12 weeks of gestation into the postnatal period. This process begins at the hilum and proceeds toward the periphery. As shown in Figure 41.1, short segments of the double-layered sleeve dilate to form tubules. As they form, individual bile ductules are incorporated into the periportal mesenchyme around the portal vein branches. These developing bile ductules consistently express cytokeratin 19 (CK19) and begin expressing cytokeratin 7 as well as other markers of differentiated biliary epithelia by 20 weeks of gestation. In contrast, precursor cells that are not associated with the differentiating ductal plate and bile ductules lose cytokeratin 19 expression. These cells maintain cytokeratin 8 and 18 production and eventually give rise to hepatocytes.
Figure 41.1 Schematic representation of the primordial ductal plate remodeling. The two layers of cells are originally separated by a slit-like lumen. Segments of the lumen dilate to form tubules, which eventually become bile ducts, incorporated into the portal tract mesenchyme. The remainder of the ductal plate involutes. In DPM, immature bile ducts persist.
Biliary differentiation involves a series of interactions between the mesenchyme surrounding the portal vein branches and the ductal plate epithelia. As a result, the ductal plate is induced to form bile ducts, which are incorporated into the portal mesenchyme. The non-tubular elements of the ductal plate involute. This remodeling of the ductal plate leads to the formation of the intrahepatic biliary tree. The largest bile ducts are formed first, followed by segmental, interlobular, and finally the smallest ductules. Arrest or derangement in remodeling leads to the persistence of primitive bile duct configurations, or to what Jorgensen termed ductal plate malformation (DPM; Figure 41.1) . Defects in ductal plate remodeling are typically accompanied by portal vein branching abnormalities. The occurrence of DPM at different generations of the developing biliary tree gives rise to different clinicopathologic entities  (Figure 41.2).
Solitary non-parasitic cysts resemble the cysts seen in fibrocystic diseases in that they are developmental rather than neoplastic in origin and are lined by simple cuboidal or columnar biliary-type epithelium (Figure 41.3). The surrounding hepatic parenchyma displays secondary atrophy, portal fibrosis, and bile duct proliferation. However, the cysts are not associated with DPM and are not seen in association with renal, pancreatic, or other cysts. Most are unilocular and do not have any clinical manifestations. When they are symptomatic, the most common presentation is that of an upper abdominal mass, although rupture, infection, or hemorrhage also may occur. Asymptomatic simple cysts do not require treatment and can be monitored by ultrasound. Intervention is only necessary if there is progressive enlargement, symptoms, or if imaging characteristics cause diagnostic uncertainty .
Figure 41.3 Solitary non-parasitic liver cyst. (A) CT demonstrating large multiloculated hepatic cyst. (B) External gross appearance of the resected cyst showing smooth, shiny surface. (C) Cut surface of the cyst demonstrating loculations. (D) Microscopically, the cyst wall is lined by AE1 cytokeratin-positive biliary epithelium. The outer part of the cyst wall contains atrophic hepatic parenchyma with portal bile duct proliferation and fibrosis.
A hereditary disorder characterized by hepatic fibrosis, portal hypertension, and renal cystic disease was described and termed congenital hepatic fibrosis (CHF) . Typically, CHF is associated with ARPKD.
In 2002, PKHD1 (polycystic kidney and hepatic disease 1) was identified as the main gene for ARPKD . PKHD1 encodes fibrocystin/polyductin which is localized to primary cilia and plays a causative role in cystic renal disease . PKHD1 is among the largest disease genes in the human genome, extending over a genomic segment of at least 470 kb and including a minimum of 86 exons. Using a technique for rapid screening of PKHD1 in ARPKD pedigrees, the detection rate of mutations was 85% in severely affected patients, 41.9% in moderate ARPKD, and 32.1% in adults with CHF or Caroli disease .
Although CHF is most commonly seen in association with ARPKD, it has also been reported as an isolated entity as well as with ADPKD and nephronophthisis . In most pedigrees, CHF is transmitted as an autosomal recessive trait. The overall prevalence of syndromes that include congenital hepatic fibrosis as a feature is estimated to be one in 10,000 to 20,000 individuals . In three families with CHF and ADPKD, pathogenic PKD1 mutations were found in all eight affected patients. Portal hypertension was the main manifestation of CHF; hepatocellular function was preserved and liver enzymes were largely normal. The presence of CHF also has been described in a variety of other rare conditions or syndromes, as listed in Table 41.1. In some of these syndromes, cystic disease of the pancreas is also observed. For purposes of discussion, a descriptive approach is taken here; this section focuses on the biliary lesion, and the renal tubular lesion is reviewed in the discussion of ARPKD.
|Fibropolycystic liver disease||Associated renal disorder|
|Congenital hepatic fibrosis|
|Caroli disease||Autosomal recessive polycystic kidney disease|
|Von Meyenburg complexes (isolated)||?|
|Von Meyenburg complexes with congenital hepatic fibrosis or Caroli syndrome||Autosomal recessive polycystic kidney disease|
|Von Meyenburg complexes with polycystic liver disease||Autosomal dominant polycystic kidney disease|
|Polycystic liver disease||Autosomal dominant polycystic kidney diseasea|
a Most common associated disorder.
The liver of patients with CHF appears grossly speckled with gray–white bands of fibrous tissue identifiable to the naked eye (Figure 41.4A,B). Microscopically, CHF is characterized by islands of normal liver that are separated by broad and narrow septa of dense, mature fibrous tissue. The fibrous tissue contains elongated or cystic spaces lined by regular biliary epithelium which represent cross-sections of the hollow structures comprising the DPM (Figure 41.4C). Prominent bands of mature fibrous tissue connect adjacent portal triads. Although the periportal fibrous is marked, the associated inflammatory cell infiltration of the portal area is usually mild. Portal vein branches often appear reduced in size and number, and the sparsity of venous channels may account in part for portal hypertension. The hepatic lesions of CHF tend to become more prominent with time, but the rate of progression is variable. The fibrosis may increase secondary of recurrent episodes of cholangitis. The fibrosis of CHF can be differentiated from cirrhosis, in which there is nodular regeneration, often inflammation and necrosis and there is no presence of biliary channels. The portal tracts in CHF are expanded by mature collagenous tissue, which forms interportal bridges that initially do not disrupt the acinar architecture and explains the absence of hepatocellular dysfunction. Progressive liver synthetic dysfunction may be related to recurrent episodes of ascending cholangitis.
The onset of signs and symptoms is variable, ranging from early childhood to the fifth or sixth decade of life, but most patients are diagnosed during adolescence or young adulthood. There are four clinical forms of CHF: portal hypertensive, which is the most common; cholangitic; mixed; and latent (Table 41.2).
|Disease||Inheritance||Gene (protein product)||Renal disease||Liver disease||Associated features|
|Autosomal recessive polycystic kidney disease||AR||PKHD1 (fibrocystin)||Cystic dilatation of collecting tubule||DPM, CHF, Caroli disease|
|Autosomal dominant polycystic kidney disease||AD||PKD1 (polycystin 1), PKD2 (polycystin 2)||Cysts from all portions of tubule||DPM, CHF, and Caroli disease rarely||Liver cysts derived from but not connected to bile ducts; intracranial and aortic aneurysms; mitral valve prolapse and other cardiac valvular defects; pancreatic cysts; colonic diverticula, inguinal hernias|
|Autosomal dominant polycystic liver disease||AD||PRKCSH (hepatocystin), SEC36||None||Cysts arising from biliary microhamartomas and periductal glands, rarely CHF||Less commonly share some of the extrarenal manifestations observed in ADPKD|
|Nephronophthisis type 3||AR||NPHP3 (nephrocystin-3)||Cysts at corticomedullary junction||CHF||Tapetoretinal degeneration|
|Jeune syndrome||AR||Loci 12p, 15q13; IFT8 (intraflagellar transport protein)||Cystic renal tubular dysplasia||CHF, Caroli disease||Short stature, skeletal dysplasia, small thorax, limb shortness, polydactyly, pelvic abnormalities|
|Joubert syndrome||AR||AH11 (jouberin), HPHP1, NPHP1-4-8 (apical surface), NPHP5-(centrosomes)||Cystic dysplasia, nephronophthisis||CHF||Dysgenesis of cerebellum, Dandy–Walker malformation, cardiac defects|
|Coach syndrome (overlap with Joubert syndrome)||AR||MKS3, CC2D2A, RPGRIP1L||Cystic dysplasia||CHF||Cerebellar vermis hypoplasia, oligophrenia (developmental delay/mental retardation), ataxia, coloboma|
|Meckel–Gruber syndrome||AR||MKS1, TMEM67, TMEM216, CEP290, CC2D2A, RPGRIP1L, B9D1, B9D2 (involved with function of cilia)||Corticomedullary cysts||DPM||CNS malformations, cardiac defects, polydactyly|
|Bardet–Biedl syndrome||AR triallelic||BBS1–8 (eight genes; M390R mutation)||Cystic dysplasia, nephronophthisis||CHF||Retinal degeneration, obesity, limb deformities, hypogonadism|
|Oral-facial-digital syndrome type 1||X-linked||OFD1 (centrosomal protein localized at the basal bodies at the origin of primary cilia)||Multiple renal medullary and cortical macrocysts||Dilatations of the intrahepatic bile ducts, CHF||Oral clefts, hamartomas or cysts of the tongue, digital anomalies, pancreatic cysts|
|Ivemark syndrome||AR||–||Cystic dysplasia||CHF, Caroli disease||Pancreatic fibrosis, situs inversus, polysplenia, cardiac and CNS anomalies|
|Congenital disorder of glycosylation-Ib||AR||PMI (phosphomannose isomerase)||None||DPM, CHF||Chronic diarrhea, protein-losing enteropthy, coagulapathy|
ADPKD, autosomal dominant polycystic kidney disease; AD, autosomal dominant; AR, autosomal recessive; CHF, congenital hepatic fibrosis; CNS, central nervous system; DPM, ductal plate malformation
The clinical manifestations of patients with portal hypertensive CHF are usually recurrent upper gastrointestinal hemorrhage from ruptured esophageal varices, splenomegaly, and hypersplenism. These episodes have been described as early as 19 months of age , although they are more commonly seen in older children. The pathogenesis of portal hypertension 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 . Although all individuals with CHF have DPM detectable by liver biopsy at birth, abnormal liver echogenicity and splenomegaly may not be detectable during early childhood because portal fibrosis and portal hypertension are time-dependent pathologies that develop and progress with age. The severity and rate of progression of CHF and its complications vary widely even within the same family, which makes prognostication difficult. Gunay–Aygun et al. described the clinical characteristics of 73 patients (aged 1–56 years) with CHF and ARPKD confirmed by detection of mutations in PKHD1. Initial symptoms were liver-related in 26% of patients, while others presented with kidney disease. Platelet count was found as the best predictor of the severity of portal hypertension. Importantly, severity of kidney and liver disease were independent of each other and disease phenotypes did not correlate with the type of PKHD1 mutation .
Patients with cholangitic CHF have an abnormal intra- and extrahepatic biliary tree. The main manifestations are cholestasis and recurrent episodes of cholangitis, which can lead to sepsis, liver dysfunction, and poor growth. Biliary stone formation and cholangiocarcinoma can develop at a relatively young age .
Pulmonary hypertension (portopulmonary hypertension) and vascular shunts in the pulmonary parenchyma (hepatopulmonary syndrome) are complications of portal hypertension that can be rarely seen in CHF. Ascites and encephalopathy are less common in CHF than in cirrhosis.
In patients with CHF uncomplicated by either portal hypertension or cholangitis, the laboratory evaluation is usually unremarkable. Serum aminotransferase and bilirubin levels are characteristically normal. Bilirubin, gamma-glutamyltransferase, and alkaline phosphatase can be elevated during episodes of cholangitis. Thrombocytopenia and neutropenia are seen in patients with portal hypertension and hypersplenism. Urea and creatinine levels may be elevated in patients with renal involvement.
Jaundice may be seen in patients with cholangitis or with deterioration of liver function. Abdominal distension can be present. The liver is enlarged and firm with a prominent left lobe and the spleen is enlarged in patients with portal hypertension.
The diagnosis of CHF can be suspected in patients with liver and renal disease, supported by imaging findings and confirmed on the basis of mutation analysis . Prenatal diagnosis of ARPKD/CHF, on the basis of haplotype analysis and on mutation analysis, has been performed . Liver biopsy can provide further characteristic findings of CHF, but its routine use is rarely required particularly in those with fibrocystic renal disease, because the diagnosis can be established on clinical findings alone. Liver biopsy may be reserved for patients with equivocal findings. Mutations in ARPKD/CHF are distributed throughout PKHD1, and polymorphisms are common. The current mutation detection rate is 80–85%. There is marked allelic heterogeneity, and most affected patients appear to be compound heterozygotes. Advances in next-generation sequencing have led to improved diagnostic capabilities in identifying PKHD1 mutations and distinguishing mutations in other genes that may mimic ARPKD. Most PKHD1 mutations are unique to single families. An ARPKD/PKHD1 mutation database has been established (www.humgen.rwth-aachen.de). Genetic diagnosis may provide guidance for personalized medical management on a gene-specific basis of patients with these diseases and may help when deciding to include the patients in clinical trials and when choosing future treatment options.
The diagnosis of CHF is suggested by ultrasound, CT, or MRI of the abdomen. Sonographically, the liver has a patchy pattern of increased echogenicity. Sonographic evaluation should include Doppler flow studies of the portal vasculature looking for evidence of portal hypertension, such as reversal of portal flow or splenomegaly. Ultrasound can demonstrate dilated ducts that often contain sludge and stones. In addition, small branches of the portal vein are often seen within the dilated ducts, each of which appears as a small, echogenic dot in the non-dependent part of the dilated duct (“central dot sign”) . Imaging with CT and/or MRI/MRCP are used for clarification and confirmation of the ultrasound findings and for demonstration of the extent of the disease. These modalities provide a more complete assessment of blood flow, visualization of the entire biliary ductal system, and better tissue characterization to improve differentiation between fibrocystic liver diseases and polycystic liver disease (PLD). Recent studies demonstrate the value of ultrasound elastography in distinguishing ARPKD from ADPKD and healthy controls, as well as correlating with presence of portal hypertension and liver disease progression [16–18]. Endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography are invasive procedures with risk of complications and are generally reserved for patients who need therapeutic intervention.
It is easy to confuse CHF with cirrhosis because of the extensive fibrosis seen on biopsy and the portal hypertension seen in CHF. Patients with CHF usually have preserved hepatic synthetic function and the pathologic findings in biopsies from these patients differ from those in biopsies of patients with cirrhosis (see “Pathology”). The bile duct strictures and dilations often seen in primary sclerosing cholangitis may be mistaken for the dilated extrahepatic bile ducts of CHF and even the intrahepatic cysts of CHF. Non-cirrhotic portal hypertension creating a nodular regenerative hyperplasia may be more difficult to distinguish from CHF than cirrhotic portal hypertension and relies on medical history, physical examination, laboratory testing, and imaging. Liver biopsy is often needed to identify intrahepatic causes of non-cirrhotic portal hypertension. Cysts in the liver, especially when few and small, may be a normal variant. The hepatic cysts seen in autosomal dominant PLD (ADPLD) are not typically associated with CHF and can be distinguished from cysts associated with CHF by the large number of cysts and the extent of involvement of the hepatic parenchyma.
Therapy depends on the type of CHF and the clinical manifestation of the disease. It is mainly supportive and is directed toward treating biliary tract infection and complications of portal hypertension. Antibiotic therapy is indicated for ascending cholangitis. However, routine antibiotic prophylaxis for cholangitis is not indicated . The treatment of biliary stones depends on their location, number, and size. Care is best provided in a tertiary care facility with expertise in managing biliary stones. Although there are theoretical reasons why choleretics such as ursodeoxycholic acid (UDCA) may impede the development of abnormalities of the bile ducts, or even fibrosis, this has not been proven and its use is not routinely recommended in children with ARPKD . Studies in the PKD rat model of ARPKD show treatment with UDCA for five months resulted in decreased hepatic cystogenesis, decreased CK19 staining and lower levels of fibrosis when compared to untreated controls. There were no significant changes in renal cystogenesis, ALT, total bilirubin, or alkaline phosphatase .
There are no evidence-based guidelines for the management of portal hypertension in children. An internationally recognized group of pediatric and adult hepatologists and surgeons developed strategies for the management of portal hypertension in children and their recommendations were updated and published after the Baveno Pediatric Satellite Meetings in 2016 . Some centers proceed with primary prophylaxis with a non-selective beta-blocker for large varices identified by surveillance endoscopy, while other centers address varices endoscopically by sclerotherapy or band ligation.
Given that liver function in CHF is usually preserved for prolonged periods, selective shunting procedures can provide relief from the complications of portal hypertension. A surgical shunt would be a strong consideration in an individual with large varices that have never bled if appropriate expert care is not available for emergency management of variceal bleeding. Liver transplantation (LT) is indicated in patients with end-stage liver disease or recurrent uncontrolled cholangitis. Shneider et al. highlight the special issues in the decision-making process regarding liver transplantation in children with liver disease (CHF or Caroli syndrome) and ARPKD . Clear-cut indications for combined liver and kidney transplantation in ARPKD included the combination of renal failure and either cholangitis or refractory complications of portal hypertension (including significant hepatopulmonary syndrome). A study by Wen et al. examined the long-term outcomes of solid organ transplant in children with fibrocystic liver-kidney diseases using the United States Scientific Registry of Transplant Recipients (SRTR) from 1990 to 2010. This retrospective study examined children that underwent an isolated LT, kidney transplant (KT) or simultaneous liver-kidney transplant (SLK) (N = 716 total; LT = 73, KT = 602, SLK = 41). The median age at first transplant was 9.7 years. Survival was not significantly different between SLK vs. LT and SLK vs. KT, although the number of SLK was small. Of note, the risk for requiring transplantation of the other organ was low (five of 73 with ESKD after liver transplant and 29 of 602 requiring LT after KT), which supports isolated transplantation over SLK in most cases . These data suggest that isolated transplantation should be strongly considered over SLK and not driven by anticipation of disease progression in the other organ.
Extrapolating from studies in adults with cirrhosis, children with CHF may be screened for esophageal varices particularly when the platelet count decreases significantly over time or prior to interventions such as renal transplantation . Small varices warrant a repeat esophagogastroduodenoscopy (EGD) in a year. If no varices are identified, EGD should be repeated within two to three years. The appropriate frequency of surveillance imaging is not well defined and depends on disease severity. For individuals with mild disease, ultrasound examination every two years would be adequate; for those with more severe disease, an annual ultrasound examination could enable adequate monitoring of disease progression. There have been several reports of liver neoplasia arising in hepatobiliary fibropolycystic diseases; the majority are cholangiocarcinomas (CCA) with some cases involving hepatocellular carcinoma (HCC) . From a large, systematic literature search, the prevalence of hepatobiliary cancer in CHF is about 2% . However, these are not issues that will present in the pediatric age group. The mean age of CCA diagnosis was 58.8 years (range 33–75 years) . No data or recommendations on surveillance for cholangiocarcinoma or hepatocellular carcinoma in pediatric CHF are available.
Once the diagnosis of CHF has been established in a proband, a family history focusing on hepatorenal fibrocystic disease, CHF/Caroli syndrome, liver or kidney disease of unknown etiology can be used to determine the inheritance pattern in an individual with CHF. If an autosomal recessive syndrome is not identified in the proband and/or the findings and/or family history suggest autosomal dominant inheritance, then ultrasound examination of parents and siblings to evaluate for the presence of asymptomatic kidney and/or liver disease characteristic of ADPKD is useful. Other evaluations, including kidney function tests, and genetic testing may be useful to establish the specific hepatorenal fibrocystic disease associated with CHF based on the abnormalities identified on family history and physical examination. For future pregnancies, pre-implantation genetic diagnosis technologies may be considered.
Autosomal recessive polycystic kidney disease is a rare and severe early-onset ciliopathy mainly caused by mutations in the PKHD1 gene. Fibrocystin/polyductin is the product of PKHD1 [6, 25]. Mutations in DZIP1L which encodes a ciliary-transition-zone protein have been described in four unrelated families with ARPKD . The disease results in loss of renal function in ~50% of patients within the first two decades of life . Despite the low incidence (1:20,000 live births), ARPKD is a major cause of end-stage renal disease necessitating renal replacement therapy in early childhood. Although ARPKD includes a spectrum of clinical and histopathologic manifestations, there are two constant features: biliary tract abnormalities arising from DPM and fusiform dilatation of the renal collecting ducts.
In affected infants, the kidneys retain their natural shape but are massively enlarged. Macroscopically, the renal surface is studded with small opalescent cysts representing the fusiform dilatation of the collecting ducts (Figure 41.5A,B). Microscopically, the dilated collecting ducts are arrayed at right angles to the capsule, and the corticomedullary junction is obscured (Figure 41.5C). In contrast, the glomeruli and other nephron segments appear normal. With time, progressive interstitial fibrosis develops, resulting in a progressive decline of renal function. The hepatic lesion in ARPKD includes enlarged, irregularly fibrotic portal areas that contain tortuous and large bile ducts associated with persistence of the ductal plate. These histopathologic findings are indistinguishable from those of isolated CHF. If the process leads to macroscopic dilatation of the intrahepatic biliary tree, it will fall into the category of Caroli syndrome (Figure 41.6). Clinically, just as in isolated CHF, the severity of the hepatic lesion varies inversely with age.
Figure 41.6 Caroli syndrome. (A) Cholangiogram of a hepatic explant with marked dilatation of the intrahepatic biliary tree. (B) Cut surface of the same liver showing both the cystic dilatation of the biliary tree and the fibrous bands throughout the liver consistent with congenital hepatic fibrosis.
Hematemesis and melena signal the presence of esophageal varices. Typically, children present with variceal bleeding at ages 5 to 13 years, but it has been reported in infants . The children may have firm hepatomegaly and splenomegaly in addition to nephromegaly. Blood urea nitrogen and serum creatinine values vary with the severity of renal involvement. Hepatic synthetic function, bilirubin, and aminotransferase values are generally normal. Anemia, leukopenia, and thrombocytopenia suggest associated hypersplenism. Although the disease phenotype is quite variable, many children have some degree of co-existent portal hypertension and chronic renal failure. The diagnosis is suggested by the clinical presentation and radiologic studies.
In the infant, ultrasound reveals massive, hyperechoic kidneys with loss of the corticomedullary junction and a variably enlarged, echogenic liver. In older children, kidney size and echogenicity are more variable, and macroscopic cysts may be evident. The liver findings by ultrasound, including Doppler studies, CT, and MRI are described in the earlier discussion on CHF. Definitive diagnosis may require renal and liver biopsies, but the diagnosis can be inferred from histology in one organ and typical sonographic findings.
Treatment for the hepatic lesions in ARPKD is the same as that described for CHF. The patients are at risk for ascending cholangitis with associated sepsis and hepatic failure; unexplained or prolonged fever may warrant diagnostic liver biopsy and culture. Although portal hypertension can be managed successfully and hepatic synthetic function is generally well preserved in ARPKD, liver transplant may be warranted in patients with chronic cholangitis. Many patients with ARPKD die in the perinatal period or during infancy from renal failure or pulmonary insufficiency. A long-term outcome study of neonatal survivors with ARPKD reported one- and five-year patient survival rates of 85% and 82%, respectively, and renal survival at five, ten, 20 years of 86%, 71%, 42%, respectively .
Caroli described two forms of congenital dilatation of the intrahepatic biliary tree associated with renal cystic disease . In the more common type, the abnormal cystic dilatation of the intrahepatic bile ducts are associated with CHF and ductal plate malformation. This entity is referred to as Caroli syndrome. The second, much rarer type is characterized by pure ductal ectasia with absence of fibrosis and is termed Caroli disease. It has been postulated that Caroli disease results from an arrest in ductal plate remodeling at the level of the larger intrahepatic bile ducts (Figure 41.2) whereas Caroli syndrome results when the full spectrum of bile duct differentiation is affected, such that the smaller interlobular ducts are involved and CHF develops. Because some reports describe changes limited to the left hepatic lobe, Caroli disease has been described in some classification schemes as either diffuse or localized.
These entities are more common in females. Both conditions are transmitted in an autosomal recessive fashion and are associated with ARPKD or, very rarely, with ADPKD . Most choledochal cysts seen in ARPKD are not related to Caroli malformations. In a study from the National Institutes of Health, 73 patients with ARPKD and CHF were described. Fifty-six percent of the patients had a dilated CBD but no intrahepatic biliary abnormalities based on high-resolution ultrasound or MRCP findings. However, 40% of children had imaging findings consistent with Caroli syndrome with variable involvement of the common bile duct .
Presenting signs and symptoms include intermittent abdominal pain and hepatomegaly. Steatorrhea has been described. In Caroli syndrome, because the lesion of CHF is also present, evidence of portal hypertension is common and usually precedes cholangitis. In both Caroli disease and syndrome, ductal ectasia predisposes to bile stagnation, with consequent sludge and stone formation and risk of infection.
The age of presentation of Caroli syndrome is highly variable. Renal symptoms and cholestasis present in infancy, while cholangitis and manifestations of portal hypertension are more likely presenting features in early childhood. Rawat et al. compared the age of presentation and the clinical symptoms of patients with Caroli syndrome (21 patients) to children with CHF (19 patients). They found that children who present in the newborn period often have Caroli syndrome and have a worse prognosis because they were likely to develop end-stage renal disease with the need for combined liver-kidney transplantation in childhood . CKD may also develop in children with Caroli syndrome who present later, and in their study, they did not require a renal transplant because their renal dysfunction was not progressive. Cholangitis adds to the significant morbidity in this patient group and itself may be an indication for liver transplantation.
Diagnosis is confirmed by imaging studies such as abdominal CT, ultrasound (Figure 41.7A) and MRCP (Figure 41.7B,C), which demonstrate irregular cystic dilatation of the large, proximal intrahepatic bile ducts. Liver biopsy is rarely required to make the diagnosis of Caroli disease or syndrome. The pathologic findings of Caroli disease may show ectasia of the larger intrahepatic ducts with features of cholangitis. Intrahepatic bile duct ectasia and proliferation with severe periportal fibrosis are the pathological features of the CHF component of Caroli syndrome.
Figure 41.7 Radiographic findings in Caroli syndrome. (A) Ultrasound of the liver demonstrating a large posterior cyst and a prominently dilated intrahepatic bile duct. The hepatic echotexture is coarse and heterogeneous. (B) MR cholangiogram, coronal oblique view, in the same patient, demonstrating the cysts noted on ultrasound as well as more diffuse involvement of the intrahepatic bile ducts. (C) The composite transverse section provides even more detail about the extent of intrahepatic bile duct dilatation.
The differential diagnosis of Caroli syndrome and disease includes primary sclerosing cholangitis, recurrent pyogenic cholangitis, obstructive biliary dilatation, PLD, and choledochal cyst. The ductal dilatation in primary sclerosing cholangitis is usually isolated and fusiform in opposition to the characteristic saccular dilatation of Caroli syndrome and disease. It may be difficult to differentiate between PLD and Caroli syndrome, as in both diseases the patients can have hepatic and renal cysts. However, the hepatic cysts of PLD do not communicate with the usually normal bile ducts and portal hypertension is rare in PLD. Cholangitis, cholelithiasis, biliary abscess, septicemia, and cholangiocarcinoma are all potential complications of Caroli syndrome and disease. The increased risk of cholangiocarcinoma in these patients has been postulated to occur because of prolonged exposure of the ductal epithelia to high concentrations of unconjugated secondary bile acids and probably to recurrent cholangitis. Liver failure secondary to recurrent cholangitis or biliary cirrhosis, liver abscesses or complications of portal hypertension increase the mortality rate of these patients.
Therapy for Caroli syndrome is similar to that for CHF. Infection is managed with antibiotics and, in severe, localized disease, lobectomy of the affected lobe. In fact, partial hepatectomy also has been shown to be effective if the biliary lesion is predominantly confined to a discrete area . Lendoire et al. reported the long-term outcome of surgical treatment of 24 adults with Caroli disease . They concluded that surgical resection was the best curative option in unilateral disease providing long-term survival free of symptoms and complications. Liver transplantation is recommended for bilobar disease with progressive decompensation of liver function and complications of portal hypertension or in the case of recurrent cholangitis and a suspicion of cholangiocarcinoma. Liver transplant may be indicated in infants as well. Kim et al. described a seven-month-old infant with Caroli disease who underwent a successful liver transplantation for recurrent cholangitis and cirrhosis . Millwala et al. published a study based on United Network for Organ Sharing data on 104 patients with Caroli disease/Caroli syndrome who received transplants between 1987 and 2006 . They showed excellent patient and graft survival similar to, or better than, that of patients receiving transplants for other causes. The overall one-, three-, and five-year graft survival rates (79.9%, 72.4%, and 72.4%, respectively) and patient survival rates (86.3%, 78.4%, and 77%, respectively) were excellent. For eight patients who received a combined liver/kidney transplantation, the one-year patient and graft survival was 100%. Millwala et al. have proposed an algorithm for evaluation and medical and surgical management of Caroli disease .
Bristowe first described the association between hepatic and renal cysts in adults in 1856 . Initially, this disorder was termed adult polycystic disease; subsequently, the nomenclature was changed to reflect the mode of genetic transmission. Autosomal dominant polycystic kidney disease is the most common hereditary renal abnormality and occurs in one in 400–1,000 individuals . Approximately 10% of patients with ADPKD will not have a positive family history of ADPKD and are presumed to have a new genetic mutation. Like ARPKD, ADPKD is characterized by renal and hepatic cysts, but ADPKD is often associated with other visceral anomalies as well. These include intracranial and aortic aneurysms, mitral valve prolapse and other cardiac valvular defects, pancreatic cysts, colonic diverticula, and inguinal hernias. ADPKD is rarely associated with CHF or Caroli syndrome; the more typical hepatic manifestation of ADPKD is PLD.
The kidneys in ADPKD contain numerous cysts of varying size in an irregular distribution, resulting in enlargement and distortion (Figure 41.8). In young children, the cysts are smaller and have a tendency to cluster; they occasionally involve the glomeruli as well as the collecting system. The kidneys of older children and adults have the more conventional findings of irregularly sized cysts distributed throughout the entire organ, with normal intervening renal parenchyma.
Figure 41.8 Autosomal dominant polycystic kidney disease. (A) MRI demonstrates the variability in size and distribution of the renal cysts, and the normal liver and biliary tree. There is a tiny hepatic cyst in the left lobe (tiny white dot) that does not appear connected to the biliary tree. (B) Resected kidney has multiple cysts deforming the capsule and obscuring the normal contour. (C) The cut surface demonstrates variable size and distribution of the cysts.
The symptomatic onset of ADPKD varies but is usually after age 40. Complications include systemic hypertension, hematuria, proteinuria, and pyelonephritis. In approximately 50% of patients with ADPKD, the renal lesion progresses to end-stage renal disease. Infection, hemorrhage, and rupture can occur in both renal and hepatic cysts.
Generally, laboratory tests are of little diagnostic value. Elevations in blood urea nitrogen and serum creatinine, as well as diminution of urinary concentrating ability, are related directly to the severity of renal involvement. Serum alkaline phosphatase is elevated in 10–20% of patients, whereas serum aminotransferases and bilirubin values are usually normal. Diagnosis requires a careful family history, assessment of clinical symptoms and signs, and imaging techniques, such as ultrasonography or CT of the abdomen; MRI is a useful diagnostic modality to identify cyst infection, hemorrhage, or calcification. Renal ultrasound is normal in about 20% of patients at 20 years of age.
In families in whom ADPKD has been identified, genetic linkage testing can be used to determine whether at-risk individuals are carrying the disease gene. The majority of ADPKD cases are due to mutation in PKD1 (Chr. 16.p13.3; approximately 78% families) and PKD2 (4p21; approximately 15%), with a rare third locus, GANAB (11q12.3; approximately 0.3%) recently identified [35, 36]. PKD1 is a very large, complex gene (46 exons) located on chromosome 16p13. It encodes the protein polycystin 1, which is a large membrane-bound protein with receptor-like properties that interacts with polycystin 2, the protein product of PKD2. Polycystin 1 is found throughout the body, including abdominal organs (kidneys, liver, pancreas), as well as heart and vasculature. Its widespread presence helps to explain the multi-organ system phenotype. PKD2 is a smaller gene (15 exons) located on chromosome 4q21-q23 and its mutations account for only 15% of ADPKD. Its product, polycystin 2, is a cation channel that modulates the concentration of intracellular calcium, an important determinant of several downstream signaling processes . The polycystin 1/polycystin 2 complexes have a major influence on cell proliferation, adhesion, apoptosis, cell matrix interactions, differentiation, tubular patterning, and cell polarity. Therefore, it is expected that cell structure and function are severely disturbed in ADPKD, resulting in the formation of cysts. The characterization of the proteins altered in ADPKD further support the central role of the cilium in the pathogenesis of PKD . Patients who have ADPKD are heterozygotes with one mutant and one wild-type allele. Therefore, it is proposed that a first-hit occurs with a germline mutation in PKD1 or PKD2 and that another somatic mutation in the wild-type allele is required to initiate cyst formation . Although GANAB (glucosidase II alpha subunit) mutations account for a small proportion of ADPKD patients , the renal phenotype associated with GANAB mutations is consistently mild without renal insufficiency, such that any kidney enlargement is due to a few large cysts .
According to an international consensus statement on ADPKD, the prevalence of hepatic cysts in children with ADPKD is <5% with no reports of severe cases . However, hepatic cysts increase in number and size with age and are present in about 50% of patients with ADPKD who have renal failure. Bae et al. reported a prevalence of hepatic cysts by MRI images in 57% of women and 60% of men between the ages of 15–25 years. Hepatic cysts were evident in 94% of patients who were older than 35 years . Hepatic cystogenesis is influenced by estrogen, with the largest cysts observed in women who have been pregnant or who have used estrogens. Hepatic cysts in ADPKD are derived from, but are not in continuity with, the biliary tract. There is little information on the effect of the type or position of mutations on the extent of hepatic cystic disease .
Most patients with liver cysts do not need treatment. Patients with severe symptomatic disease require interventions to reduce cyst volume and hepatic size. The choice of procedure (percutaneous cyst aspiration with or without sclerosis, laparoscopic cyst fenestration, combined liver resection and cyst fenestration, and liver transplantation) is dictated by the anatomy and distribution of the cysts.
Combined percutaneous cyst drainage and antibiotic treatment provide the best treatment results for hepatic cyst infections. Long-term oral antibiotic suppression or prophylaxis is indicated for relapsing or recurrent infection. Fluoroquinolones and trimethoprim–sulfamethoxazole are effective against the typical infecting organisms and have good penetration into the biliary tree and cysts .
Recently the FDA approved the use of tolvaptan, a vasopressin V2 receptor (V2 R) antagonist for the treatment of rapidly progressive disease in adults with ADPKD. Tolvaptan lowers cAMP in cystic tissues and slows renal cystic progression and kidney function decline but can cause elevation of aminotransferase enzyme concentrations with the potential for acute liver failure . The American Society of Nephrology has published guidelines regarding safety and efficacy when considering tolvaptan in adults with ADPKD , but tolvaptan is not recommended for the treatment of childhood PKD.