Introduction

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 [1], 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) [2]. 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 [3] (Figure 41.2).

Figure 41.2 Illustration showing the classifications of fibrocystic liver disease based on the duct size affected.

Solitary Non-Parasitic Cyst of the Liver

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 [4].

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.

Congenital Hepatic Fibrosis

A hereditary disorder characterized by hepatic fibrosis, portal hypertension, and renal cystic disease was described and termed congenital hepatic fibrosis (CHF) [5]. Typically, CHF is associated with ARPKD.

In 2002, PKHD1 (polycystic kidney and hepatic disease 1) was identified as the main gene for ARPKD [6]. PKHD1 encodes fibrocystin/polyductin which is localized to primary cilia and plays a causative role in cystic renal disease [7]. 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 [8].

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 [9]. 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 [10]. 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.

Pathology

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.

Figure 41.4 Congenital hepatic fibrosis. (A, B) Gross liver specimen demonstrating the prominent gray–white bands of fibrous tissue. (C) Microscopic section demonstrating dilated irregularly branching bile ducts, ductal plate malformation, and prominent portal fibrosis.

Autosomal Recessive Polycystic Kidney Disease

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 [26]. The disease results in loss of renal function in ~50% of patients within the first two decades of life [7]. 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 41.5 Autosomal recessive polycystic kidney disease. (A, B) The cut surface of the kidney demonstrates innumerable small opalescent cysts of fairly uniform size. (C) Microscopically, the cysts represent cystically dilated collecting ducts, arranged perpendicularly to the capsule.

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 [11]. 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 [7].

Caroli Disease and Caroli Syndrome

Caroli described two forms of congenital dilatation of the intrahepatic biliary tree associated with renal cystic disease [27]. 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 [28]. 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 [12].

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 [29]. 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 [30]. Lendoire et al. reported the long-term outcome of surgical treatment of 24 adults with Caroli disease [31]. 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 [32]. 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 [33]. 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 [33].

Autosomal Dominant Polycystic Kidney Disease

Bristowe first described the association between hepatic and renal cysts in adults in 1856 [1]. 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 [34]. 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 [37]. 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 [38]. 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 [39]. Although GANAB (glucosidase II alpha subunit) mutations account for a small proportion of ADPKD patients [36], 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 [40].

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 [41]. 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 [42]. 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 [43].

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 [44].

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 [45]. The American Society of Nephrology has published guidelines regarding safety and efficacy when considering tolvaptan in adults with ADPKD [46], but tolvaptan is not recommended for the treatment of childhood PKD.