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From the Archives of the AFIP Autosomal Recessive Polycystic Kidney Disease: Radiologic-Pathologic Correlation1 (CME available in print version and on RSNA Link)

LEARNING OBJECTIVES FOR TEST 6 After reading this article and taking the test, the reader will be able to: ■ Describe the renal and hepatic lesions that characterize autosomal recessive polycystic kidney disease. ■ Define the imaging features of autosomal recessive polycystic kidney disease. ■ Describe the role of imaging studies in the evaluation and diagnosis of suspected autosomal recessive polycystic kidney disease.

Gael J. Lonergan, Lt Col, USAF MC • Roy R. Rice, LCDR, USN MC Eric S. Suarez, CDR, USN MC Autosomal recessive polycystic kidney disease is a heritable but phenotypically variable disorder characterized by varying degrees of nonobstructive renal collecting duct ectasia, hepatic biliary duct ectasia and malformation, and fibrosis of both liver and kidneys. In the kidney, the dilated collecting ducts and interstitial fibrosis, when severe, may significantly impair renal function and result in hypertension and renal failure. Imaging typically shows large but reniform kidneys, diffusely increased renal parenchymal echogenicity at ultrasonography, and a striated nephrogram after contrast material administration. In the liver, periportal fibrosis accompanies the malformed and dilated bile ducts; this may result in portal hypertension. The liver may appear normal or may show intrahepatic biliary dilatation; once portal hypertension develops, splenomegaly and varices are usually evident. The relative degrees of kidney and liver involvement tend to be inverse: Children with severe renal disease usually have milder hepatic disease, and those with severe hepatic disease tend to evidence mild renal impairment. Presently, treatment consists of supportive management and control of hypertension. Replacement therapy for renal failure (dialysis or kidney transplantation) and control of portal hypertension (portal circulatory

Abbreviations: ARPKD = autosomal recessive polycystic kidney disease, CHF = congenital hepatic fibrosis, DPM = ductal plate malformation Index terms: Children, gastrointestinal tract, 76.288 • Children, genitourinary system, 81.3122 • Infants, genitourinary system, 81.3122 • Kidney, abnormalities, 81.3122 • Kidney neoplasms, 81.3122 • Liver, abnormalities, 76.288 RadioGraphics 2000; 20:837–855 1From the Department of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md (G.J.L.); the Department of Radiologic Pathology (G.J.L.) and Pediatric Pathology (E.S.S.), Armed Forces Institute of Pathology, Bldg 54, Rm M-121, 14th and Alaska Sts, NW, Washington, DC 20306-6000; and the Department of Radiology, National Naval Medical Center, Bethesda, Md (R.R.R.). Received December 20, 1999; revision requested February 14, 2000; revision received February 28; accepted March 2. Address reprint requests to G.J.L. (e-mail: [email protected]).

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official nor as reflecting the views of the Departments of the Air Force, Navy, or Defense. ©RSNA,

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diversion or liver transplantation) may be necessary. Introduction Cystic disease of the kidney comprises a heterogeneous group of conditions. Cystic disease may be broadly categorized into genetic cystic disease (autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease [ARPKD], medullary cystic disease), obstructive cystic disease (multicystic dysplasia and cystic dysplasia), acquired cystic disease (simple cysts, acquired cysts in uremia), and cysts associated with systemic disease (tuberous sclerosis and von Hippel–Lindau disease). These conditions vary widely in the nature of the cystic disease (true cysts or tubular ectasia of a portion of the nephron or collecting duct). Patient age at presentation, degree of renal functional impairment, and location and appearance of the cysts also vary considerably. Of all of the cystic renal diseases, ARPKD is the most common heritable disease manifesting in infancy and childhood and is among those that come to clinical attention earliest. The frequency of ARPKD has been reported as between one in 6,000 and one in 55,000 births (1,2). Zerres et al (3), analyzing multiple studies, estimated the frequency as one in 20,000 births and the frequency of the heterozygous carrier state as one in 70. ARPKD was first recognized as a distinct morphologic form of cystic disease in 1902 and was histologically described in 1947 (4). ARPKD was classified in 1964 in the landmark publications by Osathanondh and Potter (5,6) as type I cystic kidney disease. It was generally observed that the parents of patients with ARPKD showed no evidence of the disease, although in many families more than one child was affected. No gender predilection was noted. Therefore, it was recognized early that this disease followed an autosomal recessive inheritance pattern.

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ARPKD is a disease of tubular malformation and ectasia. In the kidney, the disorder manifests as nonobstructive collecting duct ectasia (6,7). The ducts are dilated and elongated, with 10%– 90% of them being involved, usually in a bilaterally symmetric fashion (7). When a large number of ducts are involved, the kidneys are typically enlarged. Fibrosis develops in the renal interstitium, and, when the amount of ductal ectasia and fibrosis is considerable, renal functional impairment may result (8). Hypertension, diminished urinary concentrating ability, and renal insufficiency and failure may ensue, requiring dialysis or renal transplantation (9,10). End-stage renal disease occurs in approximately 800 children per year in the United States, and ARPKD accounts for about 5% of these cases (11). Patients with ARPKD also have liver involvement, which consists of abnormal biliary ducts and portal tracts. The bile ducts are abnormally formed, often increased in number, and dilated; the portal tracts are enlarged and fibrotic (12, 13). This pattern is referred to as congenital hepatic fibrosis (CHF) and is always present in ARPKD. However, CHF has also been described in Meckel-Gruber syndrome, vaginal atresia, tuberous sclerosis, nephronophthisis, and, rarely, autosomal dominant polycystic kidney disease (13–15). Therefore, although CHF occurs inevitably in all patients with ARPKD, it is not by itself diagnostic of the disease. The most troublesome sequela of CHF is portal hypertension, although its causative mechanism is poorly understood (14). Severe portal hypertension, with splenomegaly, varices, and gastroesophageal hemorrhage, may necessitate variceal sclerotherapy, portal bypass procedures (portosystemic shunting), or liver transplantation (10). The two constant features of ARPKD are involvement of the kidney (with tubular ectasia and fibrosis) and liver (with CHF). However, the relative severity of organ involvement is quite variable. Generally, the renal and hepatic disease are inversely proportional to each other in individual patients. Children with severe kidney disease often have mild CHF and vice versa. Therefore, the features and presentation of ARPKD vary substantially. To help radiologists better understand ARPKD, we discuss the diverse clinical,

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histopathologic, radiologic, and prognostic features of this complex disease, beginning with its renal manifestations and following with its hepatobiliary features.

The Kidney in ARPKD Clinical Features The renal involvement in ARPKD is much more often the cause of clinical presentation than is liver disease, a fact reflected in the naming of the disease (7,16,17). The collecting ducts are dilated and elongated, in association with interstitial fibrosis, all of which result in smooth renal enlargement and a spongelike texture of the renal parenchyma (6,17). When the majority of ducts are abnormal, renal function is typically impaired, with azotemia and diminished urinary concentrating ability (18,19). This functional impairment may result from crowding of normal structures (such as nephrons and vessels) by the dilated ducts, from interstitial fibrosis, or, most likely, from a combination of both. The amount of renal impairment generally correlates with the amount of collecting duct involvement (9). Ectasia may affect 10%–90% of all collecting ducts; the greater the percentage of abnormal ducts, the more severe the renal compromise and the earlier the clinical presentation (7,17,19). It has long been recognized that the disease manifestations and clinical presentations of ARPKD vary considerably, even within a single family. In 1971, Blythe and Ockenden (7) published a landmark study identifying and categorizing the spectrum of ARPKD into four distinct groups—perinatal, neonatal, infantile, and juvenile—based on age at presentation, kidney size, clinical course, and amount of collecting duct dilatation. The most severe involvement occurred in the perinatal group; in these patients, the disease was recognized around the time of delivery and was characterized by huge kidneys and severe respiratory and renal compromise. Approxi-

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mately 90% of the collecting ducts were ectatic, and all infants died within the 1st week of life. Disease in the neonatal (the second) group was slightly milder and was characterized by approximately 60% duct involvement. These infants presented in the 1st month of life, and almost all died of renal failure within their 1st year. The infantile form of ARPKD (the third group) was characterized by approximately 25% duct involvement, presentation at age 3–6 months, and development of both renal failure and portal hypertension. The juvenile form (the fourth group) manifested the least renal disease (about 10% duct involvement), with little renal impairment, and patients with juvenile ARPKD presented between the ages of 6 months and 5 years with portal hypertension. This categorization of patients reflects the inverse relationship of renal and hepatic disease typical of ARPKD. Today, ARPKD is viewed as a spectrum of kidney and liver disease, and the Blythe and Ockenden classification is infrequently used. From the preceding description of the disease spectrum, it is evident that severe renal disease tends to predominate in the very young infant and may be diagnosed in utero (3,20,21). Severe renal functional impairment in the affected fetus leads to decreased fetal urine output and oligohydramnios. Pulmonary hypoplasia results, and most of these infants die from pulmonary compromise shortly after birth (16,19). Although these infants also have renal failure, it is not the proximate cause of death and it is amenable to renal replacement therapy such as dialysis or transplantation (7,17,19). The massively enlarged kidneys (which may be 10–20 times larger than normal) further compress the developing fetal lung in utero and contribute to the pulmonary hypoplasia (17,19) caused by the oligohydramnios. Oligohydramnios also results in a constella-

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a.

b.

Figure 1. Potter facies in ARPKD. (a) Frontal photograph of an infant demonstrates a snubbed nose, lowset and flattened ears, and deep eye creases. (b) Lateral photograph of another infant shows micrognathia and low-set ears. (c) Fetal US scan demonstrates a varus deformity of the foot (arrow), compatible with clubfoot.

tion of clinical findings known as Potter facies: low-set and flattened ears, short and snubbed nose, deep eye creases, and micrognathia. Extremity deformity such as club foot is also common (Fig 1) (16). With milder renal disease, the degree of renal functional impairment is less severe. The amount of amniotic fluid is nearer normal, and the kidneys are less enlarged; therefore, severe perinatal respiratory compromise is not typical. These infants tend to present at slightly older ages (but almost always within the 1st year of life) with renal impairment and hypertension. Finally, patients with very little renal disease (perhaps only 10% duct involvement) may have no renal functional impairment. In these patients, progressive hepatic fibrosis leads to the development of portal hypertension. These patients present in the first few years of life with splenomegaly and varices (7,16). It is thought that the milder forms of renal disease in ARPKD enable the patients to survive longer and to undergo the inevitable progression of CHF. Renal disease does not appear to progress as consistently as does the hepatic

c.

Figure 2. Collecting duct dilatation in ARPKD. Diagram of a renal medullary ray depicts both normal and abnormal collecting ducts. The left side of the diagram (A) depicts a normal nephron draining into a normal (nondilated) collecting duct. The right side (B) depicts a normal nephron draining into an ectatic collecting duct in ARPKD.

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nephron; in ARPKD, this occurs primarily in the collecting duct (Fig 2). Symmetric and circumferential epithelial proliferation results in tubular lengthening and fusiform dilatation of the collecting duct (9). The abnormal epithelium also manifests an unusual change in function. Whereas normal epithelium is essentially resorptive (ie, it resorbs fluid from the duct lumen and transports it across the epithelium and into the renal interstitium), abnormal proliferative epithelium paradoxically becomes secretory. The fluid secreted into the ectatic duct lumen is rich in epithelial growth factors, which stimulate further epithelial proliferation (27–29). Studies in animals with ARPKD have shown that blocking epithelial growth receptors and epithelial growth enzymes results in diminished cyst formation and tubular ectasia (28). These findings offer the hope of therapeutic intervention at the cellular level. Figure 3. Histologic features of the kidney in ARPKD. Low-power photomicrograph (original magnification, ´20; hematoxylin-eosin stain) of a renal specimen involved with ARPKD shows radially oriented, dilated collecting ducts (*) abutting the renal capsule (arrowheads). Normal glomeruli are interspersed among the dilated collecting ducts (arrows).

disease. Renal disease may remain mild for these patients, even for many decades (16,22,23). The considerable variability in phenotypic expression of this heritable disease led to early speculation that multiple genes influenced the phenotype. Recently, the gene responsible for ARPKD has been linked to chromosome 6p21 (the short arm of chromosome 6), although the gene itself has yet to be identified. This information has been used to screen high-risk pregnancies accurately as early as 13 weeks (by means of chorionic villous sampling and comparison with an affected sibling’s DNA). It is thought likely that several mutant alleles of the gene influence phenotypic expression in individual patients (24– 26).

Pathogenesis of Renal Involvement in ARPKD All renal cysts develop from focal epithelial proliferation somewhere along the course of the

Histologic and Pathologic Features At histologic analysis, the kidney with ARPKD displays numerous dilated and elongated tubular structures, radially oriented relative to the renal hilum (Fig 3) (6,8). Microscopic examination and immunostaining with peroxidase-labeled peanut (Arachis hypogaea) lectin demonstrates that these cysts and spaces are dilated collecting ducts. Microdissection studies and scanning electron microscopy show that obstruction is not the underlying cause of dilatation; the “cysts” in fact represent dilatation and hyperplasia of the interstitial portions of ureteric bud branches that form the collecting ducts. Nephron induction is unaffected, and the number of glomeruli formed is normal. On tissue sections, the density of the glomeruli appears reduced due to separation by dilated collecting ducts and by the presence of variable degrees of interstitial edema and fibrosis (8,30,31). At autopsy study, the kidneys are symmetrically enlarged and have preserved their reniform shape. Close examination of their capsular surfaces discloses multiple, minute cystic spaces throughout. On cut section, these cystic structures can be recognized as subcapsular extensions

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a. Figure 5. Nephromegaly in a newborn with ARPKD. (a) Frontal chest and abdominal radiograph shows bilateral flank masses that displace gas-filled bowel loops centrally (arrows). (b) Lateral chest and abdominal radiograph shows large retroperitoneal masses (*) that displace the gas-filled bowel loops anteriorly. (c) Autopsy photograph of the opened abdomen shows nephromegaly (curved arrows) and centrally displaced bowel. In the liver are multiple small yellow foci of portal tract fibrosis (straight arrows).

b.

c.

Figure 4. Photograph of a bivalved kidney involved with ARPKD reveals multiple ectatic collecting ducts, radially oriented from the center of the kidney to the surface. The corticomedullary junction is obliterated by the numerous abnormal ducts.

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b. Figure 6. Pulmonary hypoplasia in an infant with ARPKD. (a) Frontal chest and abdominal radiograph shows bilateral pneumothoraces (note the deep costophrenic sulci bilaterally [arrows] and unusually sharp mediastinal borders), bilateral flank masses, and centrally located bowel. (b) Autopsy photograph of the chest shows a small thorax, compatible with pulmonary hypoplasia. a.

of radially oriented cylindrical or fusiform ectatic spaces. The elongated and dilated collecting ducts extend from medulla to cortex, making the corticomedullary junction difficult, if not impossible, to discern (Fig 4) (6,8).

Radiologic Characteristics Just as the spectrum of renal involvement varies, so do the radiologic manifestations of ARPKD. The discussion herein focuses on urinary tract imaging of the neonate or infant with moderately severe renal disease and mild liver disease, and on renal imaging of the slightly older child with little kidney disease but considerable CHF. In neonates and infants with moderate to severe renal disease, the kidneys are smoothly enlarged because of the numerous dilated collecting

ducts. The degree of enlargement is directly proportional to the number of dilated ducts. Abdominal distention is evident on radiographs, and gas-filled bowel loops are often deviated centrally (Fig 5). With severe kidney disease, the baby may be born with pulmonary hypoplasia and a small thorax. Pneumothorax is common in these infants at birth and following assisted ventilation (Fig 6). At ultrasonography (US), the kidneys are smoothly enlarged and diffusely echogenic; this appearance is thought to be caused by the many interfaces between the radially arrayed dilated ducts and the ultrasound beam (Fig 7) (32–35). There is loss of corticomedullary differentiation,

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a. b. Figure 7. Fetal kidneys in ARPKD. (a) Longitudinal US scan of the left kidney in a 3rd-trimester fetus shows an enlarged, echogenic kidney (arrows) with loss of corticomedullary differentiation. Note the paucity of amniotic fluid, indicating oligohydramnios. (b) Transverse US scan of a 26-week-old fetus shows enlarged kidneys (arrows) that are more echogenic than the liver (*).

a. b. Figure 8. Urinary tract in ARPKD. (a) Longitudinal US scan of the upper portion of the right kidney (straight arrows) shows an enlarged, heterogeneous kidney that is more echogenic than the liver. The thin hypoechoic rim of tissue at the renal periphery (*) most likely represents compressed cortex. The liver (curved arrows) demonstrates heterogeneous echogenicity. (b) Excretory urogram demonstrates striated nephrograms in bilaterally enlarged kidneys, hypodense rims of parenchyma (*), and a small bladder (arrow). (c) Photograph of the autopsy specimen shows the enlarged kidneys with persistent fetal lobation and the small bladder (arrow).

c.

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a. b. Figure 9. Macrocysts in ARPKD. (a) Longitudinal US scan of an enlarged, echogenic right kidney shows several rounded, anechoic areas (*). (b) Photograph of the bivalved kidney specimen helps confirm the macrocysts (arrows). The radially arrayed, fusiform, dilated spaces throughout the remainder of the renal parenchyma are dilated collecting ducts.

although there may be a thin rim of hypoechoic parenchyma at the periphery that is presumed to be compressed cortex (Fig 8). Macrocysts may be evident; they tend to become larger and more numerous over time (Fig 9). The bladder is usually small (32,33,35,36). At unenhanced computed tomography (CT), the kidneys are smooth, enlarged, and low in attenuation, likely a reflection of the large fluid volume in the dilated ducts (37). With intravenous administration of contrast material, the kidneys show a striated pattern of contrast media excretion at excretory urography and CT (Fig 10). The striated appearance represents accumulation of contrast material in the dilated tubules (Fig 11) (33,38). If renal function is considerably impaired, there may be poor opacification and excretion, making it difficult to visualize the kidneys at excretory urography (Fig 12) (33). The few case reports of magnetic resonance (MR) imaging of ARPKD in the literature (all of fetal kid-

Figure 10. Striated nephrograms in ARPKD. Excretory urogram of a newborn with enlarged, smooth kidneys shows striation of the kidneys bilaterally, representing pooling of contrast material in dilated, radially oriented collecting ducts.

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a. b. c. Figure 11. Pattern of contrast material enhancement in ARPKD in an adolescent with mild renal insufficiency. (a) Axial unenhanced CT scan shows a normal-sized right kidney with a small calcification (arrow). (b) Axial CT scan obtained immediately after intravenous injection of contrast material shows prompt peripheral enhancement. (c) A 15-minute delayed image reveals streaks of high attenuation in the renal parenchyma, oriented radially from the renal pelvis. This finding represents excreted contrast material pooling in dilated collecting ducts.

neys) described increased signal intensity of the renal parenchyma at T2-weighted imaging (21, 39). A case report of technetium-99m dimercaptosuccinic acid radionuclide imaging of a neonate with ARPKD described diffuse, symmetric uptake of the radiopharmaceutical (40). Reports of long-term follow-up imaging of severe ARPKD are few. In one such report, nine children with neonatally diagnosed ARPKD (with 20%–75% duct involvement) were monitored over a minimum of 5 years (36). In five of these patients, the kidneys decreased in size; in three, they remained stable; and in one, they showed progressive enlargement. This study also documented that renal parenchymal echogenicity may remain stable or increase over time. Neither the renal size nor echogenicity correlated with renal function. Interestingly, this study did not note an increase in the size or number of macrocysts (36). Early in life, the liver in these children usually appears normal at imaging (and is less echogenic than kidneys), although occasionally dilated intrahepatic biliary ducts are seen, even in the neonate (33). Those children who survive the neonatal period and early infancy and who come to clinical attention later only because of portal hypertension have milder renal involvement (usually less than 50% duct involvement). Their kidneys may

Figure 12. Severe ARPKD in a newborn. Axial CT scan obtained after intravenous administration of contrast material shows large, smooth, low-attenuation kidneys (arrowheads). There is faint, streaky enhancement secondary to the infant’s renal failure, resulting in poor perfusion and excretion of contrast material.

appear normal at US, or they may show changes similar to, although usually less severe than, those of the infant with ARPKD. Therefore, their kidneys may be radiologically normal, or they may be enlarged, be echogenic, and have scattered macrocysts (41). The kidneys may demonstrate some striation of the parenchyma after contrast material enhancement but usually much less than that seen in the severely involved kidney

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Figure 13. Mild ARPKD in a 16-yearold adolescent with normal renal function. Excretory urogram shows kidneys of normal size but some striation of the nephrograms bilaterally.

(Fig 13) (34). Many of these children will have normal, or near normal, renal function. The imaging appearance of the kidneys does not appear to correlate with function (16,36,41,42). If the kidneys develop multiple macrocysts (on a background of diffusely increased echogenicity), they may mimic the appearance of autosomal dominant polycystic kidney disease. Therefore, in older children who have progressed to renal fibrosis and macrocyst formation, the appearance of the kidneys at imaging may not be diagnostic of ARPKD.

Treatment Currently, treatment for ARPKD consists of symptomatic management of the sequela of the disease. This includes control of systemic hypertension, with its attendant risk of heart failure, and renal failure. Hypertension is usually controlled with medication. Renal failure is treated with dialysis or renal transplantation (16,19). Sumfest et al (43) described bilateral nephrectomies they performed in three neonates with pulmonary hypoplasia secondary to ARPKD. The surgery (performed within the first 2 weeks of life) enabled the two children who survived to successfully undergo extubation by day 15 of life. These two children, at the time of the original report, were alive at 1 year and 2½ years of age on peritoneal dialysis and awaiting transplantation, with no reported pulmonary complications.

Prognosis Prognosis varies with the severity of renal disease. Infants born with severe renal disease (up to 90% of ducts involved) may not survive the neonatal

period because of severe pulmonary hypoplasia. Those with less severe disease who survive the neonatal period may develop renal insufficiency or end-stage renal failure, although the age at which this occurs is highly variable. One series reviewing patients initially presenting in infancy (and therefore presumably with considerable renal disease) reported that severe renal insufficiency developed in 11% of patients at 2 years of age, in 36% at 5 years, and in 100% at 20 years of age (44). However, there are many reports of patients living into adulthood with no or only mild renal insufficiency (16,22,23,45–47). Because the amount of renal involvement evidenced by patients in many of the aforementioned studies is not known, it is difficult to characterize a “typical” prognosis. Certainly, these studies demonstrate that renal function may progress to failure over years to decades, progress to insufficiency, or, rarely, may remain normal. Of note, progression to renal failure is not inevitable, especially in patients who survive infancy. Growth retardation tends to accompany renal insufficiency and failure and has been reported in 25% of children with ARPKD (48). Hypertension occurs in the majority of patients, usually early in life. One study reported this sequela in 100% of patients by age 3 months (16). Other studies reported its frequency as 61%–100% (48). In a review by Roy et al (23) of 52 patients followed up long term, 39% had hypertension by 1 year of age and 67% by 15 years of age. The survival rate in this group, calculated for those surviving the 1st month of life, was esti-

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Figure 14. Drawings illustrate the development of the ductal plate. The ductal plate initially forms as a single layer of cells around the developing portal vein (A). Another layer of cells develops, creating a double sleeve around the portal vein (B). In the next stage (C), the double-layered sleeve coalesces and remodels around the portal vein (*). The ductal plate in a normal portal tract (D) remodels into several connected bile ducts around the portal vein (*). The ductal plate in a patient with CHF (E) remodels abnormally, forming bile ducts around the portal vein (*) that are dilated, abnormally branching, and increased in number. There is fibrosis of the tissue separating the bile ducts in the portal tract.

mated as 86% by 1 year of age and 67% by 15 years of age (23). Renal calcification has been noted in patients with ARPKD from infancy to the 2nd decade of life. The largest study noted a correlation between the severity of renal calcification and renal failure (Fig 10) (49). It is theorized that calcification may be the result of either urinary stasis in dilated ducts, urine acidification defects (with resultant alkaline urine and diminished calcium solubility), or a combination of these two effects (49).

The Liver in ARPKD Clinical Features The term autosomal recessive polycystic kidney disease implies that renal disease is more common than liver disease in this entity. However, liver disease is inevitably found in patients with ARPKD. Like the renal disease, the hepatic disease is variable in its severity, age at presentation, and clinical manifestations. Two predominant features characterize the liver in ARPKD: abnormality of the biliary tree and fibrosis of the portal tracts. Abnormality of the biliary tree consists of irregularly formed, dilated, and usually too numerous intrahepatic bile ducts (these are contiguous with other portions of the biliary tree and therefore nonobstructive). Despite the abnormal bile ducts and the fibrosed portal tracts, the hepatic parenchyma is normal. Thus, it is not surprising that hepatocellular function is almost always normal in affected patients, even when they have relatively severe portal tract disease. The liver disease is referred to as CHF, which is always found in patients with ARPKD. Because CHF may be found in other diseases (eg, juvenile nephronophthisis, MeckelGruber syndrome, tuberous sclerosis, vaginal

atresia, and, rarely, autosomal dominant polycystic kidney disease), it is not pathognomonic for ARPKD (12–14). The abnormal bile ducts in CHF are often described as ductal plate malformation (DPM) (50). An understanding of liver embryology is helpful to understand DPM. The liver begins developing at 4 weeks of gestation as a ventral bud from the foregut. Hepatocyte precursor cells form from this bud. At the same time, the intrahepatic portal veins are forming. The hepatocyte precursor cells adjacent to the portal veins form a sleevelike double layer around the veins. This double-layered sleeve is the ductal plate. The ductal plate remodels over the next several weeks into individual bile ducts in the portal tracts, and any parts of the ductal plate that did not coalesce into ducts are resorbed (51). Abnormal bile duct formation and resorption (ie, abnormal remodeling of the double-layered sleeve) is called DPM. It is characterized by increased numbers of bile ducts, abnormal branching of these ducts, and variable degrees of ductal dilatation (Fig 14) (12,13,50). Part of DPM also consists of fibrosis of the portal tracts. It is unclear if the portal fibrosis is caused by abnormal resorption of remnants of the ductal plate or if it is a distinct but related entity of CHF. When the bile ducts are macroscopically dilated, ARPKD in the liver may be indistinguishable from Caroli disease (pure intrahepatic duct dilatation, without fibrosis) or Caroli syndrome (histologically identical to CHF) (13,14,52). Histochemical studies of CHF and Caroli disease show considerable overlap (53). Some investigators have hypothesized that CHF and Caroli disease represent a spectrum of portal tract malformations, with one end being portal fibrosis with normal-caliber ducts (CHF) and the other end being pure ductal dilatation with no portal fibrosis (Caroli disease) (54,55).

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a. b. Figure 15. Histologic features of the liver in ARPKD. (a) Low-power photomicrograph (original magnification, ´75; hematoxylin-eosin stain) of a liver specimen shows an enlarged portal tract (curved arrows) with increased numbers of irregular, branching bile ducts (straight arrows), surrounded by lighter pink staining portal fibrosis. The hepatic parenchyma (*) is normal. (b) Medium-power photomicrograph (original magnification, ´140; trichrome stain) shows blue-staining periportal fibrosis in a portal tract (arrows), within which are multiple dilated bile ducts (*).

In the liver, CHF most often results in portal hypertension, although the causative factors have not been definitively identified (13). Some studies indicate that the abnormally remodeled sleeve of DPM, with too numerous, dilated, and irregularly branching bile ducts, exerts mild pressure on the portal veins, thus resulting in portal hypertension. Other studies suggest that the mass effect of the portal tract fibrosis exerts pressure on the portal veins. The number of portal venules in DPM may also be abnormally reduced, which could in itself result in portal hypertension (13, 56). Inflammatory infiltrates have been documented in the portal tracts of patients with CHF; this, too, has been theorized to lead to portal hypertension by causing destructive cholangiopathy and inflammatory changes of the portal tracts (12,50,53). Although the mechanism of portal hypertension development in CHF is not yet fully elucidated, it is the most common sequela of CHF. When the degree of portal hypertension is clinically evident, patients may present with splenomegaly, variceal bleeding, and hypersplenism (leukopenia, thrombocytopenia, and anemia) (9). The age at which these conditions occurs is highly variable. Most commonly, patients present between the ages of 5 and 13 years. However, varices have been noted in neonates, and some cases of CHF do not come to clinical attention until adulthood (14,57). The severity of CHF and portal hypertension is also quite variable. Notably, all patients with ARPKD, irrespective of clinical disease, will have findings of CHF at liver biopsy (13). CHF is believed by many to be

an almost inevitably progressive condition, resulting in portal hypertension in the vast majority of patients over time (8,9,13,58,59). CHF and portal hypertension may in fact be the predominant manifestations of ARPKD in those patients with minimal renal disease. Because it tends to be milder in infancy and young childhood (when more severe renal disease tends to bring the patient to clinical attention), CHF tends to be the presenting form of ARPKD in older children and adults. CHF may also result in ascending cholangitis, which is presumed to be caused by entry of nonsterile gastrointestinal contents into the dilated intrahepatic bile ducts. It is more common (and may be recurrent) in patients with macroscopically dilated bile ducts (13,50,53,60,61). Patients with cholangitis present with abdominal pain, fever, and elevation in levels of hepatic enzymes. ARPKD has been linked to chromosome 6p, and it appears that a single gene (with multiple alleles) codes for the development of ARPKD in all its varied manifestations, including hepatic and renal disease. From the previous discussion, it is evident that there is overlap between CHF and other entities (eg, Caroli syndrome and autosomal dominant polycystic kidney disease) (24, 25). It is intriguing to theorize that a single gene with many alleles codes for the development of a spectrum of fibropolycystic diseases of the kidney and liver. Despite intensive investigation, no

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Figures 17, 18. (17) Mild intrahepatic biliary dilatation. (a) Axial contrast material–enhanced CT scan shows mild intrahepatic biliary dilatation (arrows). (b) Corresponding radiograph obtained during cholangiography helps confirm the mildly and irregularly dilated intrahepatic biliary tree. (18) Severe intrahepatic biliary dilatation. (a) Axial contrast-enhanced CT scan demonstrates multiple large, rounded, low-attenuation areas in the liver. The spleen is also enlarged. (b) Photograph of a resected liver specimen shows that these spaces are dilated intrahepatic bile ducts. The yellow material within the dilated ducts is bile.

17a.

17b.

18a.

18b.

single genetic locus has been identified to date.

appearance may be evident on cut surfaces. This appearance is caused by the periportal fibrosis, which appears as septa in the hepatic parenchyma (Fig 16). Regenerating nodules are not seen (12).

Histologic and Pathologic Features The portal tracts show variable degrees of fibrosis and angulated bile ducts with mild dilatation (Fig 15). Serial sections show that these biliary structures, rather than being actual ducts, correspond to interconnected cisterns or disk-shaped dilatations, indicative of DPM. The hepatic parenchyma is typically normal in appearance. Inflammatory infiltrates in the periportal tissue are usually mild (12). The liver is usually of normal size. A puckered

Radiologic Characteristics Imaging findings of the hepatobiliary manifestations of ARPKD, as with those of the renal manifestations, are variable. The discussion herein emphasizes the radiologic findings associated with CHF in patients of various ages. At US, the usually normal-sized liver typically displays patchy or diffusely increased echogenicity (Fig 8). Occasionally, distinct increased echogenicity of the portal tracts is seen, a finding

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Figure 19. Moderate intrahepatic biliary dilatation. (a) Transverse US scan of the liver (arrows) shows large, elongated anechoic spaces (*). (b) Axial contrast-enhanced CT scan shows rounded, low-attenuation areas in the liver (arrows). (c) Delayed (60-minute) frontal image from an iminodiacetic acid radionuclide study demonstrates patchy distribution and excretion of the radiopharmaceutical in the liver (arrowheads), which has flowed into the small intestine (arrows), a finding which confirms that the biliary dilatation is nonobstructive. The patchy appearance probably represents excretion into dilated bile ducts, with pooling of the radiopharmaceutical. (d) Radiograph of the resected liver specimen, obtained after its biliary tree was injected with iodinated contrast material, reveals the intrahepatic biliary dilatation.

a.

c.

b.

d.

Figure 16. Photograph of a cut liver section removed from an adolescent with ARPKD as part of a liver transplantation shows macroscopically dilated intrahepatic bile ducts (arrows) and a puckered surface, due to retractile bands of periportal fibrosis.

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b. Figure 20. Varices in ARPKD. (a) Esophagogram demonstrates several serpiginous filling defects (arrows) in the lower esophagus, consistent with esophageal varices. (b) Axial contrast-enhanced CT scan obtained through the upper abdomen shows enlarged and tortuous splenic veins (arrows), indicating portal hypertension.

that is believed to represent periportal fibrosis. The intrahepatic biliary tree may appear normal at US and CT or may be dilated; usually, the degree of dilatation is mild, although considerable intrahepatic biliary dilatation is occasionally seen, even in neonates (Figs 17–19) (8,42,62). Recently, MR cholangiography has been studied as a means to evaluate macroscopic intrahepatic biliary dilatation. MR cholangiography was found to be more sensitive than US in the detection of dilated bile ducts in children with ARPKD (63). As children and adults with ARPKD develop more severe portal hypertension, the liver may become enlarged (8,42). Splenomegaly is also frequently seen in patients with portal hypertension. In addition, esophageal varices may be demonstrated with upper gastrointestinal series, and enlarged splenic and portal veins may be seen at US and CT (Fig 20) (41,42). Doppler US interrogation of the portal and splenic veins may help assess the direction of flow (hepatofugal or hepatopetal) and therefore the progression of portal hypertension (14).

Treatment Treatment of the hepatobiliary manifestations of ARPKD consists primarily of control of variceal bleeding. Sclerotherapy has been shown to be

a.

very effective in controlling bleeding (23,46). Occasionally, placement of portosystemic shunts is necessary to reduce bleeding and the formation of additional varices. Although surgical morbidity is high, patients with ARPKD otherwise appear to tolerate shunt placement well; the frequency of hepatic encephalopathy in these patients is low (59). In rare cases, liver transplantation is necessary in patients with severe hepatic dysfunction or chronic cholangitis (14). Hypersplenism may be treated with splenectomy (23,46). The other significant complication in ARPKD is ascending cholangitis, which tends to recur and may lead to hepatic abscess formation, sepsis, and death. Prompt management with antibiotics and, when indicated, surgical drainage (and possibly lobectomy) helps reduce morbidity and mortality (14,64).

Prognosis The long-term outcome for patients with CHF is not well documented in the literature. The largest study to date followed up 52 patients with neonatally diagnosed ARPKD for varying time intervals (23). Of these patients, 24 died (eight from end-stage renal failure, seven from respiratory failure, four from variceal bleeding, one from sepsis, two postoperatively from transplant rejec-

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tion, one in adulthood from cardiovascular disease, and one in childhood from a motor vehicle accident). In the 35 patients in this series known to have survived beyond 1 year of age, hepatomegaly was seen in 83% and variceal bleeding occurred in 23%, at a mean age of 12½ years (death occurred in four of these patients). None of the surviving patients had evidence of hepatocellular failure. Seven of the 35 patients developed hypersplenism (23). Another study reported on seven adults with ARPKD (17–31 years of age), five of whom were treated with renal replacement therapy. Of these seven patients, five developed portal hypertension and two of them eventually developed recurrent variceal bleeding that required sclerotherapy. Hypersplenism occurred in six patients, and one had recurrent cholangitis (46). In another series, fatal cholangitis was reported (65). From these reports, it is evident that although portal hypertension is relatively common, variceal bleeding also occurs in a minority of patients. Most patients who survive childhood have a relatively good prognosis (16,23,46).

Summary ARPKD is a disorder of renal collecting duct and intrahepatic biliary dilatation, associated with fibrosis of the kidney and liver. It is a phenotypically diverse disorder, displaying variable severity of renal and hepatic involvement. When the renal disease is severe, ARPKD tends to manifest in the first months of life and may be seen in utero accompanied by oligohydramnios from decreased fetal urine production. These severely affected infants are often born with pulmonary hypoplasia and suffer from respiratory compromise. Many do not survive the neonatal period. For those children born with milder renal involvement, most will develop some degree of renal insufficiency, and some will progress to renal failure. A few will maintain normal renal function into adulthood. It is difficult to predict which children will progress and which will maintain relatively normal renal function. In the liver, ARPKD tends to be mild in infancy and early childhood. The hepatic involvement is progressive, however, and these children usually develop signs of portal hypertension from their CHF. Most patients usually present between the ages of 5 and 13 years, but some do not come to clinical attention until adulthood.

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Fortunately, portal hypertension and variceal bleeding are usually not life threatening, and many of these patients live into midlife. Because both the renal and hepatic involvement in ARPKD tend to progress, most patients, if they survive to adulthood, will develop renal insufficiency and portal hypertension, although progression is not inevitable. Recent investigation into the causes of tubular hyperplasia holds some promise for early therapy. Early intervention may help slow or arrest some features of the disease, extending the life expectancy and quality of life for affected individuals.

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